Comprehensive Organic Functional Group Transformations II: v. 6(Carbon with Three or Four Attached Heteroatoms )

&2035(+(16,9(25*$1,& )81&7,21$/*5283 75$16)250$7,216,, (GLWRUVLQ&KLHI $5.DWULW]N\8QLYHUVLW\RI)ORULGD *DLQHVYLOOH86$ 5-.7D\ORU'HSDUWPHQWRI&KHPLVWU\ 8QLYHUVLW\RI100  C) a double ring-opening process to give poly(ether esters) 26 takes place, at low temperatures (100 °C i, ii

n

n

O

O

O

O

n

R

iii. –20 °C

TMS PEt3 PEt3 Et3P Rh Rh Et3P PEt3 Et3P TMS

ð41Þ

142 143

Treatment of a solution of dimethyl(trimethylsilylmethyl)phosphonate in TMEDA at
78  C with 2.5 equiv. of BunLi gave the crystalline dilithiated phosphonate 144, whose X-ray crystal structure revealed a highly aggregated species that is characterized by a Li
O
Li
O fourmembered ring at its core (Equation (42)) . O (MeO)2P

TMS

i. 2.5 BunLi, TMEDA, –78 °C; ii. rt, 24 h

O (MeO)2P Li

+. . – TMS . N(Me)2 . (Li (TMEDA)2) (TMEDA) Li 2 3 2

144

ð42Þ

Functions Containing at Least One Group 15 Element

377

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1998POL2029

Functions Containing at Least One Group 15 Element

379

Biographical sketch

Shahrokh Saba was born in Tehran, Iran, studied at the American University of Beirut, in Lebanon where he obtained his B.S. in 1970. He continued his education at the University of East Anglia and received his Ph.D. in 1974 under the direction of Professor A. R. Katritzky. During 1975–1979 he taught as an Assistant Professor at Azad University in Tehran. He moved to the United Stated in 1980 and after postdoctoral fellowships in 1980 (Professor R. Breslow, Columbia University), 1981 (Professor W. C. Agosta, Rockefeller University), and 1982–1983 (Professor N. O. Smith, Fordham University) assumed a teaching position at Kean College, New Jersey in 1984. He returned to Fordham University in 1986 and took up his present position, and is currently an Associate Professor of chemistry. His scientific interests include all aspects of heterocyclic chemistry, and new uses of simple ammonium salts in organic synthesis.

James A. Ciaccio was born in Newburgh, NY, studied at SUNY, Oneonta where he obtained a B.S. in chemistry. His graduate studies in organic chemistry were conducted at SUNY, Stony Brook, where he obtained a Ph.D. under the direction of Professor T. W. Bell. In 1989 he was awarded a Camille and Henry Dreyfus Postdoctoral Teaching and Research Fellowship at Bucknell University, where he was Visiting Assistant Professor of Chemistry while working in the laboratories of Prof. H. W. Heine. During 1989–1990 he taught as Visiting Assistant Professor of Chemistry at Bard College, after which he took up his present position at Fordham University, where he is currently Associate Professor of Chemistry and Director of the General Science Program. His scientific interests fall in the general area of organic synthetic methods with emphasis on reactions and synthesis of epoxides and other heterocycles. He has also published several novel undergraduate organic laboratory experiments that combine synthesis and mechanistic discovery.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 355–379

6.13 Functions Containing at Least One Metalloid (Si, Ge, or B) and No Halogen, Chalcogen, or Group 15 Element; Also Functions Containing Four Metals P. D. LICKISS Imperial College London, London, UK 6.13.1 METHANES CONTAINING AT LEAST ONE METALLOID (AND NO HALOGEN, CHALCOGEN, OR GROUP 15 ELEMENT) 6.13.1.1 Methanes Bearing Four Metalloid Functions 6.13.1.1.1 Four similar metalloid functions 6.13.1.1.2 Three similar and one different metalloid functions 6.13.1.1.3 Two similar and two different metalloid functions 6.13.1.2 Methanes Bearing Three Metalloid Functions and a Metal Function 6.13.1.2.1 Three similar metalloid functions 6.13.1.2.2 Other mixed metalloid functions 6.13.1.3 Methanes Bearing Two Metalloid and Two Metal Functions 6.13.1.3.1 Two Si and two metal functions 6.13.1.3.2 Two Ge and two metal functions 6.13.1.3.3 Two B and two metal functions 6.13.1.3.4 Other combinations of two metalloids and two metal functions 6.13.1.4 Methanes Bearing One Metalloid and Three Metal Functions 6.13.1.4.1 One Si and three metal functions 6.13.1.4.2 One Ge and three metal functions 6.13.1.4.3 One B and three metal functions 6.13.2 METHANES BEARING FOUR METAL FUNCTIONS 6.13.2.1 Methanes Bearing Four Similar Metals 6.13.2.2 Methanes Bearing Three Similar and One Different Metal Functions 6.13.2.3 Methanes Bearing Two Similar and Two Different Metal Functions 6.13.2.4 Methanes Bearing Four Different Metal Functions 6.13.3 METHANES BEARING MORE THAN FOUR METALLOID OR METAL FUNCTIONS

381

382 382 382 387 388 389 389 401 402 402 402 402 403 403 403 403 403 403 403 403 404 404 404

382 6.13.1

Functions Containing at Least One Metalloid (Si, Ge, or B) METHANES CONTAINING AT LEAST ONE METALLOID (AND NO HALOGEN, CHALCOGEN, OR GROUP 15 ELEMENT)

The structure of this chapter is based closely on the corresponding one in COFGT (1995), where it was noted that for the 47 different elements (i.e., not the elements specifically excluded in the title of the section, the lanthanides, the actinides, and Fr, Ra, and Tc) that were to be considered as substituents at a quaternary carbon, there are 230 300 different possible combinations of the metal substituents (not including a further 178 365 optical isomers generated by having four different elements as substituents). The number of these possible combinations discussed later is still below 0.1% of those possible thus indicating that there is still tremendous scope for the synthesis of such organometallic compounds. For the case of methanes bearing four metal substituents, it has been necessary to make some judgment about whether the species may be of interest to organic chemists. For example, compounds where the carbon is part of a metal carbide have been excluded.

6.13.1.1

Methanes Bearing Four Metalloid Functions

There are hundreds of compounds known containing a carbon substituted by four silyl groups. The many methods to prepare them have not developed much beyond those described in COFGT (1995), but some new variations of reagents and experimental conditions mean that yields are often improved. The surprising lack of compounds with no tetragermyl substitution at carbon was noted in COFGT (1995). Although this is no longer the case, very few compounds of this type are known even now. This is still presumably due to a lack of synthetic effort as many of the methods available for tetrasilylmethane synthesis should be suitable for the preparation of tetragermylmethanes. A small number of methanes substituted by four boron functions have been prepared and there are an increasing range of compounds containing either a variety of metalloid functions or mixed metalloid and metal functions.

6.13.1.1.1

Four similar metalloid functions

(i) Four Si functions (a) Tetrasilylmethanes from in situ coupling reactions. Symmetrical compounds containing the Si4C function may be prepared by in situ coupling reactions involving CCl4 or CBr4 and a group 1 or 2 metal. These reactions are discussed in more detail in . A few new examples have been reported recently; for example, the use of 4,40 -di-t-butylbiphenyl as a catalyst in the reaction of CCl4 with lithium powder at low temperature gives an 80% yield of (Me3Si)4C , which is much better than that without the catalyst. The in situ method has also been used in the preparation of the spirocyclic compound 1 in 25% yield (Equation (1)) . These syntheses rely on the relatively slow coupling reactions to form disilanes using Li or Mg and should be applicable to a wider range of silanes as long as the substituents are not too bulky. SiMe2Cl + SiMe2Cl

CCl4

+

Mg

Me2 Si C Si Me2

Me2 Si Si Me2

ð1Þ

1

(b) Formation by reaction between a trisilyllithiomethane and a halosilane. The reactions between trisilyllithiomethanes (for their synthesis, see Section 6.13.1.2.1 below) and halosilanes have been used to prepare a wide range of tetrasilylmethanes in which there are at least two different silyl substituents on the carbon. Such compounds are not accessible via the in situ coupling reaction, which produces only symmetrical compounds. This method is thus more general and often gives good yields. The only potential difficulty with these reactions is that the Si3CLi-substituted precursor may require stringent low-temperature conditions for its preparation.

Functions Containing at Least One Metalloid (Si, Ge, or B)

383

The bulk of a trisilyllithiomethane derivative together with the low-temperature preparations means that it is possible to prepare reagents containing functional groups that would not normally be compatible in simpler compounds. For example, reagents containing both Si
H and C
Li groups are accessible and can be used to give a range of compounds containing Si
H groups that can then be used as precursors to many other tetrasilylmethanes. The range of trisilylithium reagents available for these reactions, together with the products available, is given in Table 1. As would be expected from simple metathesis reactions, the yields for this method are usually good. The order in which the silyl substituents are attached to the central carbon may be important if the groups are particularly bulky, and it seems best if the most bulky silyl substituent is not the one to be attached last. It should also be noted that addition of more than 1 equiv. of a trisilylmethyllithium reagent to a polyhalosilane does not result in more than monosubstitution at silicon; presumably this is due to the steric crowding at the relatively small silicon center. The reaction of (HMe2Si)3CLi with SiCl4 gives several products (see Table 1), the main one being the cyclic species 2, in approximately 38% yield . The generation of compounds containing more complicated tetrasilylmethane centers by this general route is exemplified by the syntheses of the bicyclic compounds 5 and 6 shown in Scheme 1 . In this case, the intermediate organometallic reagent, 4, derived from the trisilylmethane derivative 3, is probably the potassium derivative in THF solution. In a related reaction to those described above, the treatment of the Grignard-like species [Mg(OEt)2{C(SiMe3)3}I]2 with Me3SiCl gives (Me3Si)4C in 23% yield .

Me2 Si (HMe2Si)2C C(SiMe2H)2 Si Me2 2 Me2 Si Me2Si

H

Me2Si

C

BuLi/ButOK

SiMe2

Me2Si Me2Si

Me2 Si

H 3

Si Me2

SiMe2

Me2Si

THF, – 40 °C

C

M C

C H

Me2Si 4

Si Me2

RMe2SiCl Me2 Si Me2Si

Me2 Si

SiMe3 C SiMe2

Me2Si C

Me2Si Me3Si

Me2Si

R = Me

Si Me2

i. BuLi/ButOK ii. Me 3SiCl

C

SiMe2

Me2Si Me2Si

C H

98%

6

SiMe2R

Si Me2

R = Me, 82% R = Ph, 90 % R = CH2CH2CH2Cl, 86 %

5

Scheme 1

(c) Formation via addition reactions of silenes. The dimerization of silenes, Si¼C containing compounds, occurs readily at room temperature and usually gives head–tail dimers. If there are two silyl substituents at the unsaturated carbon center, then the resulting dimers contain two tetrasilylmethane centers. The silenes (Ph2MeSi)(Me3Si)C¼SiMe2 and (Me3Si)2C¼SiPh2 undergo Ph and Me group migrations to give a mixture of isomeric silenes that dimerize in the head-to-tail fashion to give the disilacyclobutanes 7–10 in varying yields depending on the nature of the silene starting material. The silene (Me3Si)2C¼SiMe2 dimerizes in a similar manner .

Table 1 Lithiomethane

Tetrasilylmethanes from the reaction of miscellaneous trisilyllithiomethanes with halosilanes

Halosilane

Product

R2C(SiMe2Ph)Li R2C(SiPh2Me)Lia

PhMeHSiCl Me2SiHCl

R2C(SiMe2Ph)(SiPhMeH) R2C(SiPh2Me)(SiMe2H)

R2C(SiPh2Me)Li R3CLi R3CLi

Me3SiCl EtSiCl3 BunSiCl3

R3CSiPh2Me R3CSiEtCl2 R3CSi(Bun)Cl2

R3CLi R3CLi R3CLi R3CLi R3CLi R3CLi R3CLi R3CLi

(p-MeOC6H4)SiCl3 (p-MeOC6H4)MeSiF2 (p-MeOC6H4)2SiF2 Si2Cl6 Me3SiCl Me2SiHCl CH2¼CHMeSiCl2 (p-MeOC6H4)2SiMeHCl

R3CSi(p-MeOC6H4)Cl2 R3CSiMe(p-MeOC6H4)F R3CSi(p-MeOC6H4)2F R3CSi2Cl4CR3 R4C R3CSiMe2H R3CSiMeClCH¼CH2 R3CSi(p-MeOC6H4)MeH

R3CLi

(p-MeC6H4)2SiMeHCl

R3CSi(p-MeC6H4)MeH

R3CLi R2C(SiMe2H)Li

Ph2SiF2 Me3SiCl

R3CSiPh2F R3CSiMe2H

R2C(SiMe2H)Li R2C(SiMe2H)Li R2C(SiMe2OPh)Li R2C(SiMe2SPh)li R2C(SiMe2SMe)Li (HMe2Si)3CLi (HMe2Si)3CLi (HMe2Si)3CLi (HMe2Si)3CLi (HMe2Si)3CLi (HMe2Si)3CLi (HMe2Si)3CLi (HMe2Si)3CLi (HMe2Si)3CLi (HMe2Si)3CLi (PriMe2Si)3CLi

Me2SiHCl Me2PhSiCl Me2SiHCl Me2SiHCl Me2SiHCl Me3SiCl MeSiHCl2 HSiCl3 MeSiCl3 SiCl4 SiCl4 CH2¼CHMe2SiCl CH2¼CHMeSiCl2 CH2¼CHCH2MeSiCl2 [CH2¼CH(CH2)4]Me2SiCl Me2SiHCl

R2C(SiMe2H)2 R2C(SiMe2Ph)(SiMe2H) R2C(SiMe2OPh)(SiMe2H) R2C(SiMe2SPh)(SiMe2H) R2C(SiMe2SMe)(SiMe2H) (HMe2Si)3CR (HMe2Si)3CSiMeHCl (HMe2Si)3CSiHCl2 (HMe2Si)3CSiMeCl2 (HMe2Si)3CSiHCl2b (HMe2Si)3CSiMe2CH(SiMe2H)2b (HMe2Si)3CSiMe2CH¼CH2 (HMe2Si)3CSiMeClCH¼CH2 (HMe2Si)3CSiMeClCH2CH¼CH2 (HMe2Si)3CSiMe2[(CH2)4CH¼CH2] (PriMe2Si)3CSiMe2H

Yield (%)

References

40 40



48 60 70 62 72 82 82 40 45

a

R ¼ Me3Si.

b

Formed as a mixture, together with compound 2.

30 63 69 64 47 43 31 98 91 20 96 26 8 89 85 87 92 77

385

Functions Containing at Least One Metalloid (Si, Ge, or B) Me2 Si

Me3Si C

SiMe3 C

SiMe2

R2 C

R2

R2

Me2 Si

SiMe3 C

SiMe2

R1 C

R2

Me2 Si

SiMe3 C

SiMe2

R1 C

R2

R1

Me3Si 7

Me2 Si

R1 C

SiMe2

R1

R1 9

8

10

R1 = SiMe2Ph R2 = SiMePh2

Photolysis or thermolysis of diazomethane precursors gives rise to the silenes 11, which undergo intramolecular head-to-tail additions to give the cyclic species 12 in low yield as components of complicated product mixtures (Equation (2)) . Reaction of PhSiCl3 with {Li[C(PMe2)(SiMe3)2]}2xTMEDA occurs to give the phospha-alkene 13, which on prolonged reaction times or on storage gives 14 via a complicated mechanism thought to involve loss of PMe2Cl, formation of a silene intermediate, and both Me and SiMe3 migrations (Equation (3)) .

Me2Si PhMe2Si

Me2 Me 2 Si Si

SiMe2

(

Si Me2

)

PhMe2Si

SiMe2Ph

C SiMe2Ph

C

n

( SiMe )

11

2

ð2Þ

n

n = 1 or 2 12 Ph Me Si SiMe3 (Me3Si)2C Me2Si PMe2

Me3Si Ph Me3Si Si P C(SiMe3)2 Me2 P Cl Me2 13

ð3Þ

14

Addition of Me3SiN3 to the THF adduct of the silene (But2MeSi)(Me3Si)C¼SiMe2 leads not to a cycloaddition but the formation (But2MeSi)(Me3Si)2CSiMe2N3 in 15% yield together with diazo-containing products . Addition of a lithium reagent to a silene can also occur, thus reaction of TsiLi(Tsi=(Me3Si)3C) with the silene (Me3Si)2C¼SiMe2, at
95  C followed by warming to room temperature and work-up in the air affords (Me3Si)2CHSiMe2Tsi . (d) Thermolytic or photolytic methods. Interest in the thermolysis of low-molecular-weight silanes to give complicated cyclic compounds has waned in recent years but the thermolysis of (Cl3Si)2CCl2 in a fluidized bed of Si/Cu has been revisited and shown to afford (Cl3Si)4C and the cyclic compounds 15 and 16 . Similarly, thermolysis of the trisilacyclohexane derivative 17 over Si/Cu gives compounds 18 and 19 (Equation (4)) . Cl2Si

SiCl2 Cl2 Si C C Si SiCl3 Cl3Si Cl2

Cl2 Si Cl3Si C C Cl3Si Si Cl2

16 n = 0, 1, or 2

15

Cl2Si

SiCl2 Si Cl2 17

330 °C Si/Cu

Cl2 Si SiCl3 C Si n SiCl3 Cl2

Cl2Si

SiCl2 C SiCl3 Si SiCl3 Cl2 18

Cl2 Si +

Cl2Si

Cl2 Si C C Si Si Cl2 Cl2 19

Cl2 Si SiCl2 Si Cl2

ð4Þ

386

Functions Containing at Least One Metalloid (Si, Ge, or B)

(e) Other methods. No recent examples of transition metal catalyzed syntheses or carbosilane rearrangements catalyzed by AlBr3 as methods for preparing tetrasilylmethanes seem to have been published. These methods are discussed in . The reaction between Me3GeSiCl3 and phosphaalkenes 20 led to an unusual P¼C bond cleavage and the formation of the cyclic species 21 (Equation (5)) . Me3Si

P

Me3Si

PPriR1

Cl2 Si Me3Si C P PPriR1 Me3Si Si Cl2

Toluene 2 h, rt

20

ð5Þ

21

R1 = Pri or But

(ii) Four Ge functions The surprising absence of tetragermylmethane derivatives was noted in the reference and was attributed to a lack of synthetic effort in this area rather than to any inherent instability of such compounds. More recently, a need for the synthesis of tetragermylmethanes has been generated by the semiconductor and chemical vapor deposition community and this has led to the preparation of a small number of these compounds. The synthesis of (BrCl2Ge)4C and (Br3Ge)4C can be achieved in 80% and 95% yields, respectively, via the insertion of GeX2dioxane (where X = Cl or Br, respectively) into the C
Br bonds of CBr4 . Reduction of these perhalo compounds with LiAlH4 gives (H3Ge)4C in 20% yield, which has been used as a precursor to various semiconductor materials via thermal decomposition .

(iii) Four B functions Compounds containing the CB4 grouping in which the C
B bonds are simple two-center twoelectron bonds are rare, much more common are the polyhedral carboranes where multicenter bonding predominates. This chapter will not discuss carboranes, more information about them can be found in several reviews . One of the very few preparations of a tetraboramethane derivative is shown in Equation (6), in which a boriranylideneborane, 22, reacts with tetrahalodiboranes. If the substituents at boron are aryl rather than alkyl, then products containing the CB2Si2 grouping are formed (see Section 6.13.1.1.3) . But B

B

But

Hexane

+ B2X4 (Me3Si)2C

–85 °C

C 22

X But Me3Si B B X C C Me3Si B X B X But

ð6Þ

X = Cl, 92%; X = Br, 82%

Despite the lack of synthetic interest in simple compounds containing the CB4 grouping, there has been theoretical interest as the computational search for species containing planar four-coordinate carbon reveals that the ‘‘boraplane’’ 23 does have a D4h arrangement at the central carbon. An experimental confirmation of this planarity does not seem to have been carried out .

B

B C

B

B

23

387

Functions Containing at Least One Metalloid (Si, Ge, or B) 6.13.1.1.2

Three similar and one different metalloid functions

(i) Three Si functions and one Ge function The ready availability of trisilyllithiomethane derivatives (see Section 6.13.1.2.(i).(a) below) would suggest that the easiest route to Si3GeC compounds is the reaction of a germyl halide with an Si3CLi derivative. The reaction of (Me3Si)3CLi with GeCl4 in THF gives the expected (Me3Si)3CGeCl3 , and the reaction of 1 equiv. of (Me3Si)3CLi with GeBr4 in toluene solution affords (Me3Si)3CGeBr3 but use of a 2:1 ratio of reagents does not give rise to [(Me3Si)3C]2GeBr2 but rather to (Me3Si)3C(PhCH2)GeBr2 in 64% yield. This is thought to be due to a loss of Tsi from the initially formed [(Me3Si)3C]2GeBr2 followed by formation of PhCH2 from the solvent and radical recombination of PhCH2 and (Me3Si)3CGeBr2 . Reaction of (Me3Si)3CLi with GeCl2 dioxane in THF solution gives the germylene [(Me3Si)3C]ClGe:LiCl3THF in 41% yield, which undergoes ready reaction with alkenes or with phenyl acetylene to give Ge(IV) products 24 and 25 resulting from (2+1)-cycloadditions (Scheme 2). A novel bicyclic digermane, 26, is formed on reduction of 25a with Mg/MgBr2 (Scheme 2) . Reaction of (Me3Si)2(2-NC5H4Me2Si)CLi with GeCl2 dioxane gives the monomeric organogermanium(II) chloride 27 in 72% yield . As in the case of [(Me3Si)3C]ClGe:LiCl3THF, the usual dimerization expected for such species is prevented by the steric protection afforded by the three bulky silyl substituents, intramolecular coordination via the pyridyl nitrogen also prevents an increase in coordination number at the Ge atom. The first structurally characterized organometallic ate complex of Ge(II), 28, has been prepared in 40% yield from the reaction of (Me3Si)3CLi with Ge(SBun)2 .

Ph

Cl Cl Tsi Ge Ge Tsi

H

Ph

Tsi Ge:.LiCl.THF Cl

Tsi = (Me3Si)3C

R1 R2

H

24

Cl Cl Tsi Ge Ge Tsi

H R3

R1

R2

H

R3

Mg/MgBr2 Ethylene, 25a

Tsi Ge

Ge Tsi

26, 68%

25a, R1 = R2 = R3 = H b, R1 = R2 = H, R3 = Me c, R1 = R2 = H, R3 = Ph d, R1 = R2 = Me, R3 = H

Scheme 2

Me2Si Me3Si C Me3Si

BuS Me3Si SBu THF Me3Si C Ge Li S THF Me3Si S

N Ge Cl

27

28

(ii) Three Si functions and one B function Relatively few new syntheses of compounds containing the Si3BC grouping were reported in the 1990s; most of the recent chemistry of such compounds deriving from compounds prepared before COFGT (1995) was published. The most obvious route to Si3BC-containing compounds is to treat a boron trihalide with a trisilyllithium reagent. Thus, the reaction between (Me3Si)3CLi and BCl3 gives the expected monosubstituted product (Me3Si)3CBCl2. Substitutions at the B
Cl bonds may then be carried out to generate further compounds containing the Si3BC grouping . A more complicated route has been found to be the addition of a silylene

388

Functions Containing at Least One Metalloid (Si, Ge, or B)

to an unsaturated species. Thus, addition of Me2Si: to Me
B¼C(SiMe3)2 is thought to lead initially to a three-membered ring, which undergoes further reaction with a second equivalent of Me
B¼C(SiMe3)2 to give ring expansion and the formation of 29 in 77% yield . Me2 Si C(SiMe3)2 (Me3Si)2C B B Me Me 29

(iii) Three Ge functions and one Si or B function; also three B functions and one Si or Ge function Considering the dearth of compounds containing the CGe4 function, it is, perhaps, not surprising that there are a few trigermylmethyl derivatives known. Only one compound, (Me3Ge)3CSiBut2F, containing the CGe3Si grouping seems to have been prepared. It can be made in 20% yield by reaction of (Me3Ge)2(FBut2Si)CLi2THF with Me3GeCl . No doubt many other derivatives could be prepared in a similar way. No compounds with the CGe3B grouping seem to be known. Again, this lack of compounds is not likely to be due to a problem of inherent instability of such species but rather a lack of interest in their synthesis. Apart from the silyl- and germyl-substituted carboranes, there is a lack of CB3Si or CB3Ge functions, which is surprising when one considers that several compounds containing the CB4 function are known (see Section 6.13.1.1.1). However, the first triboracyclobutane 30 can be prepared according to Equation (7) from the triboracyclobutanide 31 in 50% yield . The synthesis of these mixed metalloid compounds could probably be easily achieved in a manner similar to those already known, i.e., via metathetical reactions between a metalloid-substituted methyllithium derivative and an element halide. SiMe3 Me3Si

Dur

C B B B Dur 31

6.13.1.1.3

CH2SiMe3 +

Li

Cl2BCH2SiMe3

–LiCl

C Dur

B

Me3SiCH2 B Cl Dur = duryl, 2,3,5,6-Me4C6H

B

Dur

B

ð7Þ

CH2SiMe3 30

Two similar and two different metalloid functions

(i) Two Si and two Ge functions When one considers that there are a large number of compounds containing the CSi4 function and a few CGe4 function known, it might be expected that there will only be a handful of compounds known that contain the CSi2Ge2 function. This is indeed the case. Such compounds have been prepared using methods that have been widely used for the synthesis of CSi4 functions and many more species could no doubt be prepared in similar ways. Little work has been done with these compounds since that reported in , but more examples of the elimination of LiX from XMe2GeCLi(SiMe3)2 compounds (where X = F, Br, OMe, or OPh) to give Me2Ge¼C(SiMe3)2, which dimerizes to give the head-to-tail dimer [Me2Ge
C(SiMe3)2]2, have been reported .

(ii) Two Si, one Ge, and one B functions Compounds containing the CSi2GeB function do not appear to be known. They are likely, however, to be readily available from the reaction of one of the several known CSi2GeLi containing compounds with a boron halide or B(OMe)3.

389

Functions Containing at Least One Metalloid (Si, Ge, or B) (iii) Two Si and two B functions

There are very few compounds known containing the CSi2B2 grouping but two such compounds have been prepared using addition reactions to unsaturated boranes. Thus reaction of methylideneborane 32 with the three-membered species 33 gives the five-membered species 34 in 81% yield (Equation (8)) and the borataalkyne 35 reacts with Me2SiHCl to give the bicyclo[1.1.1]pentane derivative 36 in 73% yield (Equation (9)) . But N Me B C(SiMe3)2

Bu

But N

t

B

+ But

32

B

B

But

Me

B

B

But

C SiMe 3 SiMe3

33

ð8Þ

34 Me mes – – B C B mes Me3Si 2 Li+ SiMe3

–2 LiCl + 2Me2SiHCl

–Me2SiH2

Me3Si

C

Me Si B B

C SiMe3 mes

ð9Þ

mes

35

36

The boriranylideneboranes 37 react with B2Cl4 to give the unsaturated species 38 (Equation (10)). If the substituent on boron is But rather than the aromatic group, then B4C-containing species are produced, see Section 6.13.1.1.1 . Ar

Ar

Ar B

B

Hexane +

(Me3Si)2C

C

B2Cl4

–85 °C

Cl

Me3Si Me3Si C B Cl2B

Cl Ar

ð10Þ

37 38, Ar = C6Me4H, 50% Ar = C6Me3H2, 33%

(iv) Two Ge and two B functions; two Ge, one Si, and one B functions; and two B, one Si, and one Ge functions As might be expected from the paucity of CSi2Ge2 and CSi2B2 containing species, there appear to have been no compounds prepared containing the CGe2B2, CGe2SiB, or CB2SiGe functions. Again, there is unlikely to be any good reason why such compounds should not be made. Reactions between appropriately substituted lithiomethanes and halometalloids should readily afford the required functions.

6.13.1.2 6.13.1.2.1

Methanes Bearing Three Metalloid Functions and a Metal Function Three similar metalloid functions

(i) Three Si functions (a) Three Si and one group 1 metal functions. There has been a surge of interest in the preparation and use of trisilyllithiomethane derivatives because of the previous widespread application of (Me3Si)3CLi and (PhMe2Si)3CLi as bulky alkyl group transfer reagents popularized by Eaborn and Smith . The chemistry and structures of compounds containing these bulky groups have been reviewed. Table 2 gives details of how many of the trisilyllithium lithium reagents available may be prepared. Several general points can be made. There are two main

Table 2 Trisilyllithiomethanes from the reactions of trisilylmethane derivatives and various metallating agents Trisilylmethane derivative R3CH R3CH R3CCl (HMe2Si)3CH (PriMe2Si)3CH (Ph2PCH2Me2Si)3CH (Ph2PMe2Si)3CH (Me2NMe2Si)3CH (o-MeC6H4Me2Si)3CH [(EtO)3Si]3CH R2(CyMe2Si)CH R2(PhMe2Si)CH R2(PhMe2Si)CH R2(PhMe2Si)CH R2(PhMe2Si)CH R2(Ph2MeSi)CH R2(2-C5H4NMe2Si)CH R2(MeOMe2Si)CCl R(MeOMe2Si)2CH R(MeOMe2Si)2CH R2(BrMe2Si)CBr R(FMe2Si)(But3Si)CBr R(TfOMe2Si)(But3Si)CBr R2(Ph2PMe2Si)CH R2(Ph2PCH2Me2Si)CH R2(Me2NMe2Si)CCl R2(Me2NMe2Si)CH R(Me2NMe2Si)2CH [(Me3Si)2CHSiMe2]2O [HCR2SiMe2CH2]2 [HCR2SiMe2CH2]2 a R = Me3Si. examples.

b

a

Metallating agent and conditions

Trisilyllithiomethane product

MeLi, THF/Et2O BunLi, hexane Li, toluene, 85–90  C LDA, THF MeLi, THF, 48 h reflux MeLi BuLi, hexane, TMEDA MeLi, THF BuLi, petroleum, TMEDA ButLi, THF, –65  C MeLi, THF MeLi, Et2O MeLi, THF/TMEDA MeLi, THF MeLi, petroleum/TMEDA MeLi, THF/Et2O, 4 h reflux, MeLi, THF BuLi, THF,
78  C MeLi LDA PhLi, low temp. 2 PhLi 2 BunLi MeLi MeLi BuLi, THF, –78  C MeLi, THF BuLi MeLi, THF MeLi, THF/TMEDA MeLi, THF

R3CLi R3CLi, base-free R3CLi, base-free (HMe2Si)3CLi (PriMe2Si)3CLi 41 [Li(TMEDA)2][(Ph2PMe2Si)3C] [(Me2NMe2Si)2CLi]1 [Li(TMEDA)2][(o-MeC6H4Me2Si)3CLi] [(EtO)3Si]3CLi R2(CyMe2Si)CLiTHF R2(PhMe2Si)CLiEt2O R2(PhMe2Si)CLiTMEDA R2(PhMe2Si)CLi2THF R2(PhMe2Si)CLiTMEDA R2(Ph2MeSi)CH 39 R2(MeOMe2Si)CLi2THF mixtureb R(MeOMe2Si)2CLi R2(BrMe2Si)CLic R(PhMe2Si)(But3Si)CLi R(BuMe2Si)(But3Si)CLi R2(Ph2PMe2Si)CLi2THF 42 40 40 R(Me2NMe2Si)2CLi 43 [Li(TMEDA)2]+ salt of 44 [Li(THF)4]+ salt of 44

Reaction occurs at both the methine C
H and at Si
OMe bonds.

c

Yield (%)

86 66 65 84 92 54 54

67 90

75 ca. 90 87 59 53 90 79 43

References

This lithium species eliminates LiBr at room temperature to give the silene (Me3Si)2C¼SiMe2, see text for other related

391

Functions Containing at Least One Metalloid (Si, Ge, or B)

synthetic routes, metallation of an Si3C
H substituted carbon, usually by MeLi or BuLi, and treatment of an Si3C
X (X = Cl or Br) substituted carbon with lithium metal. The first method is more common as it is often easier to make the Si3C
H grouping compared to the corresponding Si3C
X and complications arising from the incorporation of LiX into reactions following the preparation of the trisilylmethyllithium reagent are avoided. The yields given in Table 2 are for lithium reagents isolated as solids and fully characterized. The yield of those species without an entry in the yield column can be determined indirectly from the yields of derivatives from subsequent reactions. There has been interest in recent years in the preparation of ‘‘base-free’’ trisilylmethyllithium reagents, i.e., not containing coordinated solvent such as THF or Et2O that can either react or be incorporated into products in further reactions. Such syntheses are carried out in alkane or aromatic solvents and the reagent formed usually contains no solvent, the lithium atoms being coordinated by alkyl or aryl groups within the trisilylmethyl substituent. Another extension to this area has been the preparation of reagents containing one or more potentially reactive or coordinating groups within the trisilylmethyl group. Thus, groups such as (RMe2Si)(Me3Si)2C, where R = OMe, NMe2, 2-pyridyl, or PPh2, can be transferred via their lithium derivatives to a range of transition metal centers where intramolecular coordination by the group R promotes monomer formation and discourages formation of oligomeric species. This synthetically useful range of reagents will no doubt be expanded in the future to include other more complicated ligating groups. A recent example, (Me3Si)2(HMe2Si)CLi(THF)2, containing a reactive Si
H group can be prepared by treating (Me3Si)2(HMe2Si)CH with MeLi . The various methods for the preparation of TsiLi, the most popular of the trisilyllithium reagents, have been described in , but some new variations are included in Table 2. Sublimation of TsiLi2THF gives a small amount of TsiLi1.5THF while reaction of base-free TsiLi with O2 in toluene gives (Me3Si)2C¼O, which forms a 1:1 adduct with TsiLi to give TsiLiO¼C(SiMe3)2 . Solid-state 7Li NMR studies of base-free TsiLi and some of its adducts have also been carried out in order to investigate further the range of structures adopted by this useful reagent . The presence of coordinating groups in the trisilylmethyl substituent leads to species in which intramolecular coordination occurs to give monomeric species such as 39–41 (see Table 2 for details of the syntheses) in which some or all of the coordinating solvent is excluded. Despite the wide variety of structures that have found to be adopted by these species in the solid state, they all act as simple trisilylmethyl derivative transfer agents in solution. The use of these reagents in the synthesis of trisilylmetallamethane derivatives is detailed extensively in following sections. If two readily metallated carbons are present in a molecule, then a double metallation can occur as shown by compounds 42–44. Compound 43 is a molecular species containing an unusual interaction between the relatively low-basicity siloxane oxygen and a lithium, and the [Li(TMEDA)2]+ salt of anion 44 can be used to make a range of divalent organometallic complexes as detailed in the following sections.

N Me2Si Me3Si C Li THF Me3Si 39 Me2 Li(THF)2 Si Me3Si C PPh2 Me3Si Li THF

Me2Si

40

Me2Si (THF)2Li O Me2Si

Ph2 P Ph2 Li P C

Ph2 P

Me2Si NMe2 Me3Si C Li(THF)2 Me3Si

41

SiMe3 C SiMe3 Li C SiMe 3

Me2Si (Me3Si)2C

SiMe2

SiMe2 SiMe2 C(SiMe3)2

Li

SiMe3 42

43

44

Although few examples of polycyclic trisilyllithiomethanes have been reported recently (compared to the many described in ), the bicyclic species 3 can be monometallated, then derivatized and then metallated at the second methine center and further derivatized as shown in Scheme 1 above. A further series of trisilyllithiomethanes that have received detailed study are of the general form (XR2Si)CLi(SiMe3)2 where R is an alkyl or aryl group and X is an electronegative function such as halide or alkoxide. As might be expected, these compounds need to be prepared at low temperature as they readily eliminate LiX (at different temperatures depending on the nature of X) to give silenes R2Si¼C(SiMe3)2. For example,

392

Functions Containing at Least One Metalloid (Si, Ge, or B)

reaction between (XPh2Si)(Me3Si)2CBr (X = F or Br) with BuLi or PhLi at
78  C in Et2O gives (XPh2Si)(Me3Si)2CLi, which then generate Ph2Si¼C(SiMe3)2 and (XMe2Si)(Me3Si)2CBr (X = alkoxide or halide) react with BuLi or PhLi at low temperature to give (XMe2Si)(Me3Si)2Cli, which can then be used to generate Me2Si¼C(SiMe3)2 . Trisilyllithiomethane derivatives sometimes result unexpectedly from complicated reactions and rearrangements, the relative stability of trisilylmethyl anions perhaps being a driving force for this. For example, (Me3Si)2(HMe2Si)CLi is found to be an intermediate in the reaction between MeLi and Me3SiSiMe3 , and the disilylmethane derivative (MeOMe2Si)2CH2 reacts with ButLi in pentane at
78  C to give (MeOMe2Si)2CHLi, which undergoes a remarkable skeletal rearrangement to give the previously prepared dimer 45 (intra- and intermolecular coordination of Li in [{LiC(SiMe2OMe)3}2]; methyl groups have been omitted for clarity) in 64% yield . O

Si

O

Si

Li

O Si

C Si Si

O O

C Li

Si O

45

The popular synthetic use of trisilylmethyllithium derivatives, particularly in transition metal chemistry, has prompted the synthesis of similar species incorporating heavier group 1 metals. Clearly, such compounds are likely to be more difficult to prepare being intolerant of ether solvents, and will be more difficult to handle because of their sensitivity toward water and oxygen. Despite these problems there are now well-characterized sodium, potassium, rubidium, and caesium derivatives of trisilylmethanes, some of which have been shown to be synthetically useful. Sodium derivatives can be prepared in a similar way to some of their lithium analogs, for example, (PhMe2Si)(Me3Si)2CH reacts with MeNa in petroleum containing TMEDA to give (PhMe2Si)(Me3Si)2CNaTMEDA in 34% yield . Alkali metal exchange may also be a useful synthetic route in preparing sodium compounds; thus, reaction of (Ph2PMe2Si)(Me3Si)2CLi2THF reacts with ButONa to give (Ph2PMe2Si)(Me3Si)2CNa in which the sodium is coordinated to both the carbanionic center and to a phenyl group . In the search for stable silenes, even more bulky trisilylmethane derivatives have been prepared, e.g., treatment of (FMe2Si)(But3Si)(Me3Si)CBr with But3SiNa affords (FMe2Si)(But3Si)(Me3Si)CNa, which can then potentially eliminate NaF . Trisilylmethylpotassium derivatives can be prepared in a similar manner to the analogous lithium compounds. Thus, reaction of TsiH with MeK in Et2O in the presence of TMEDA gives TsiKTMEDA in 34% yield, (Me3Si)2(PhMe2Si)CH reacts with MeK in Et2O at
20  C to give (Me3Si)2(PhMe2Si)CK in 60% yield , and (MeOMe2Si)2(Me3Si)CH reacts with MeK to give (MeOMe2Si)2(Me3Si)CK cleanly . If (Me3Si)2(PhMe2Si)CK is crystallized from benzene, orange crystals of the potassate [K(C6H6)][K{C(SiMe3)2(SiPhMe2)}2] may be isolated . The reactivity of the potassium compounds can be shown from the reaction of the vinyl derivative, (Me3Si)2(CH2¼CHMe2Si)CK (prepared from (Me3Si)2(CH2¼CHMe2Si)CH and MeK) with adventitious silicone grease in its container over a period of 4 weeks to give [K(SiMe2O)7][K{C(SiMe3)2(SiMe2CH2¼CH)}2] . Alkali-metal exchange may also be useful as a synthetic route, species 39 reacts with ButOK to give the potassium analog (2-C5H4NMe2Si)(Me3Si)2CK which contains no solvent, the potassium being coordinated as shown in 46 in a polymeric structure .

Me2Si C

N Me2Si

N

K

K

C

Me3Si SiMe3 Me3Si SiMe3 46

Functions Containing at Least One Metalloid (Si, Ge, or B)

393

The [Li(THF)4]+ salt of 44 can also be used in the preparation of the dipotassium species 47, or a benzene solvate of the same species, 48 can be prepared directly from 49 as shown in Scheme 3 . The dicaesium compound 50 can be prepared in a similar manner .

[Li(THF)4] 44

MeLi, THF

ButOK, THF

CH2Me2Si(Me3Si)2CK(THF)2 CH2Me2Si(Me3Si)2CK(THF)2

CH2Me2Si(Me3Si)2CH CH2Me2Si(Me3Si)2CH 49 MeK, C6H6

i. MeCs, Et2O ii. Cryst. from C6H6

CH2Me2Si(Me3Si)2CK(C6H6) CH2Me2Si(Me3Si)2CK(C6H6)

47

CH2Me2Si(Me3Si)2CCs(C6H6) CH2Me2Si(Me3Si)2CCs(C6H6) 50

48

Scheme 3

Rare examples of structurally characterized alkylrubidium and caesium derivatives can be made using the reaction between MeM (M = Rb or Cs), prepared in situ from MeLi and the corresponding alkali-metal-2-ethylhexoxide, and TsiH. Thus, TsiRb is prepared in 64% yield and comprises an infinite chain of alternating planar Tsi
anions and Rb+ cations, and TsiCs crystallizes from benzene to give TsiCs3.5C6H6 in which the Cs is coordinated to both the carbanion center and three benzene molecules . Similar reactions but using (PhMe2Si)3CH as starting material give (PhMe2Si)3CRb and (PhMe2Si)3CCs in yields of 74 and 66%, respectively . The structure of the rubidium species shows that the rubidium is coordinated by the aromatic groups of the trisilylmethyl substituent. The uses of these Na, K, Rb, and Cs derivatives of trisilylmethanes are largely unexplored but the widespread use of the Li analogs suggests that they may well have significant potential, particularly in organometallic chemistry. (b) Three Si and one group 2 metal functions. The reaction of (Me2NMe2Si)3CI with Mg in Et2O gives (Me2NMe2Si)3CMgI in 54% yield. Although it has the general Grignard reagent formula of RMgX, a structural study has shown that the central carbanionic carbon has a planar environment and that there is in fact no significant C
Mg interaction, the coordination sphere of the Mg comprising three nitrogen and one iodide ligand . The reaction of (MeOMe2Si)(Me3Si)2CI with Mg in Et2O is thought to give the Grignard reagent (MeOMe2Si)(Me3Si)2CMgI, which decomposes to give the dialkylmagnesium species Mg{C(SiMe3)2(SiMe2OMe)}2 in 50% yield together with MgI2(OEt2)2. The Grignard compound can however be isolated in 80% yield from the reaction between (MeOMe2Si)(Me3Si)2CI and Mg in toluene solution . A variety of other more complicated organomagnesium complexes containing solvent are also available from similar preparative routes. Thus, reaction of reagent 39 (see Section 6.13.1.2.1 above) with MgBr2 gives 51 but with [MgBr2(OEt2)2] the Li is retained to give complex 52 . The ate complex, [Li(TMEDA)2][Li{C(SiMe3)2(SiMe2Ph)}2], reacts with MgBr2 in THF solution to give 53 in poor yield . Grignard reagents 54 are formed when R3CI species (R = Me3Si or PhMe2Si) react with activated magnesium and an unusual, unsymmetrical dialkylmagnesium compound, 55, is obtained in 95% yield from the reaction between [MgBr2(OEt2)2] and the lithium reagent formed from BuLi and (Me2NMe2Si)(Me3Si)2CI in Et2O with .

N Me2Si Me3Si C Mg THF Me3Si Br 51

Me2 THF Br N N Me2Si Mg Li (PhMe2Si)(Me3Si)2C Me3Si C Mg Br Br N Me3Si Me2 Br Li(THF)3 53 52 NMe2

Me2Si

R3C I OEt2 Mg Mg Et2O CR3 I

Me3Si C Mg OEt 2 Me3Si Bu

54, R = Me3Si or PhMe2Si

55

394

Functions Containing at Least One Metalloid (Si, Ge, or B)

The steric protection afforded by the Tsi group is seen clearly in the isolation of Tsi2Ca, the first solvent-free dialkylcalcium compound to be structurally characterized and which is obtained from the reaction between 2 equiv. of TsiK and 1 equiv. of CaI2 in 87% yield . Use of a bulky trisilyllithium reagent containing a group capable of intramolecular coordination allows the preparation of simple, monomeric dialkyl derivatives of strontium and barium. Thus, reaction of 2 equiv. of (MeOMe2Si)(Me3Si)2CK with MI2 (M = Sr or Ba) in THF affords [(MeOMe2Si)(Me3Si)2C]2M(THF)n, which when crystallized from methylcyclohexane, for M = Sr, gives [(MeOMe2Si)(Me3Si)2C]2Sr(THF) in 72% yield, and when crystallized from (Me2SiO)3/DME, for M = Ba, gives [(MeOMe2Si)(Me3Si)2C]2Ba(DME) in 68% yield . (c) Three Si and one group 12 metal functions. Reaction between TsiLi and ZnCl2 affords TsiZnCl in 26% yield as an isolated product after sublimation of the initially formed [Li(THF)4] [(TsiZn)2Cl3] . This is presumably also an intermediate in the sequential treatment of ZnCl2 with TsiLi followed by LiP(SiMe3)2 to give TsiZnP(SiMe3)2 in 60% yield . Reaction of the trisilyllithiomethane derivative 39 containing a potentially chelating group with ZnBr2 or CdCl2 gives the halide-bridged dimers 56 and 57 in 67% and 69% yields respectively and reaction of reagent 40 with ZnBr2 affords an analogous cyclic dimer . The monomeric species 58 M = Zn is formed in 60% yield from the reaction of the [Li(TMEDA)2] salt of the diorganolithiate ion 44 with ZnCl2 . A series of crowded diorganomercury compounds have been prepared by metathesis reactions. Thus, TsiHgR compounds can be prepared by reaction of TsiHgBr with RMgX (R = Me, Pri, Bun, But, or Ph) and (PhMe2Si)3CHgR compounds from (PhMe2Si)3CHgCl and RLi (R = Me, Pri, Bun, But, or Ph). Treatment of (PhMe2Si)3CHgCl with TsiLi gives the extremely bulky (PhMe2Si)3CHgTsi in 21% yield. The symmetrical dialkylmercury derivative [(Me3Si)2(HMe2Si)C]2Hg is obtained in 16% yield from the reaction between HgCl2 and (Me3Si)2(HMe2Si)CLi at
110  C . Other congested organomercury compounds containing potentially chelating groups can also be prepared by simple metathesis reactions. Thus, reaction between (MeOMe2Si)2Me3SiCK and HgBr2 gives (MeOMe2Si)2Me3SiCHgBr in 31% yield , reaction of 40 with HgBr2 gives [(Me2NMe2Si)(Me3Si)2C]2Hg in 51% yield , reaction of 39 with HgCl2 gives 59 in 62% yield , and reaction of the [Li(TMEDA)2] salt of the diorganolithiate ion 44 with HgBr2 gives a 91% yield of 60 .

N Me2Si Me3Si C M X SiMe3 Me3Si X M C SiMe3 N SiMe2

SiMe2 C(SiMe3)2

Me2Si (Me3Si)2C M

58, M = Zn 60, M = Hg

N Me2Si Me3Si C Hg Cl Me3Si 59

56, M = Zn, X = Br 57, M = Cd, X = Cl

(d) Three Si and one group 13 metal functions. There has been increasing interest in compounds containing a Si3MC grouping (where M = Al, Ga, In, or Tl) and several such compounds have been found to be useful precursors to a wide range of novel organometallic compounds. The synthesis of these compounds relies largely on metathesis reactions between a bulky trisilyllithium reagent [for their synthesis see Section 6.13.1.2.1.(i).(a)] and a metal halide. One potential problem with this synthetic method is that coordinating solvents, such as THF or Et2O that are convenient to use in the synthesis of the organolithium reagent, may be cleaved by strong Lewis acidic group 13 compounds. For example, the reaction of TsiLi with BX3 (X = F, Cl, or Br) in Et2O affords TsiOEt and not TsiBX2 species . This problem can be avoided by the use of base-free trisilyllithium reagents [for their synthesis see Section 6.13.1.2.1.(i).(a)]. The reactions between bulky trisilyllithium reagents and aluminum halides give the products expected from metathesis reactions. For example, TsiAlMe2THF is formed in 85% yield from the reaction between TsiLi2THF and Me2AlCl in THF and the solventfree TsiAlMe2 is formed in 68% yield when base-free TsiLi in toluene is used . Similarly, reaction of (CyMe2Si)(Me3Si)2CLiTHF (Cy = cyclohexyl) with Me2AlCl gives (CyMe2Si)(Me3Si)2CAlMe2THF in 88% yield and which has been used to

Functions Containing at Least One Metalloid (Si, Ge, or B)

395

prepare a range of other (CyMe2Si)(Me3Si)2CAlX2 derivatives . The dimethyl derivative TsiAlMe2THF is also a useful precursor to other crowded alanes. For example, the reaction with Me3SnX (X = F or Cl) gives TsiAlX2THF, and with Br2 or I2 gives TsiAlBr2THF and TsiAlI2THF, respectively . Reduction of TsiAlI2THF by NaK alloy gives the tetrahedrane [TsiAl]4, analogous to the tetrahedranes of Ga, In, and Tl described below . Base-free TsiLi reacts with AlCl3 at
78  C in a 1:1 ratio to give Li[TsiAlCl3] in 83% yield but if 2 equiv. of TsiLi are used then a methylation occurs to give TsiAlMeCl . If a coordinating group is present in the trisilyllithium reagent or the aluminum halide, then solvent may be excluded from the coordination sphere of the aluminum in the product. For example, reaction of 40 with AlCl3 generates 61 in 91% yield , reaction of (Me2NMe2Si)3CLi with AlCl3 in toluene containing THF gives 62 as a colorless solid in almost quantitative yield , and the product, 63, in Equation (11) is formed in 50% yield in THF solution . However, the weaker basic OMe site in 64, derived from the reaction of (Me3Si)2(MeOMe2Si)CLi2THF with AlCl3 in 62% yield, does not prevent THF from coordinating to the Al . Me2Si NMe2 Me3Si C Al Cl Me3Si Cl

Me2 Me2NMe2Si Si NMe2 C Me2NMe2Si Al Cl2

61

(Me3Si)3CLi

62

+

NMe2

Cl Me3Si Me3Si C Al Cl MeOMe2Si THF 64

THF, –78 °C

NMe2 Al

Al Cl2

Cl

C(SiMe3)3

ð11Þ

63

Bulky trisilyllithium reagents have also been used to prepare sterically hindered aluminum hydrides, which are often monomeric in contrast to species containing less sterically demanding substituents. For example, the treatment of TsiLi with H3AlNMe3 readily affords TsiAlH2THF in 86% yield . Several trisilyllithium reagents, (RMe2Si)(Me3Si)2CLi (where R = Me, Ph, or NMe2), react with LiAlH4 in THF to give cyclic dimers 65 . These structures all incorporate THF, excluding, in the case where R = NMe2, coordination of aluminum by the nitrogen. Treatment of the dimers where R = Me or Ph with Me3SiCl gives the simple hydrides (RMe2Si)(Me3Si)2CAlH2THF in 40% and 50% yields, respectively . Reaction of 65, where R = Me, with 4 equiv. of 2,6-Pri2C6H3OH gives the diaryloxo species 66 in 75% yield and with Ph3SiOH the monomeric 67 is formed in 98% yield . The trisilyllithium reagent (MeOMe2Si)(Me3Si)2CLi2THF reacts with LiAlH4 in THF to give 68 in which the weakly basic SiOMe group does coordinate to the Li to exclude coordination by a second THF molecule . (The structure of 68 was later found to be dimeric .) The reaction of (MeOMe2Si)2(Me3Si)CLi with LiAlH4 gives [Li(THF)4][(MeOMe2Si)2(Me3Si)CAlH3] .

H (RMe2Si)(Me3Si)2C Al H H

(THF)2 Li H H Al H C(SiMe3)2(SiMe2R) Li (THF)2 R = Me, 64% 65 R = Ph, 56% R = NMe2, 95%

OSiPh3 (Me3Si)3C Al OSiPh3 THF 67

R

R THF Li O O Al H Tsi R R R = Pri 66 Me3Si Me3Si

C

Al H2 Me2Si 68

H O Li Me THF

396

Functions Containing at Least One Metalloid (Si, Ge, or B)

Some remarkable polymetallic compounds have been isolated from the reaction between TsiLi and the gallium(I) halide GaBr. Thus, the reaction in toluene/THF at
78  C affords the lithium salt of the anion [Ga19Tsi6]
in 30% yield and a small amount of the fused tetrahedrane derivative 69 . The [Ga19Tsi6]
anion contains a central Ga13 metal core surrounded by six Tsi–Ga substituents. Use of the simpler, related tetrahedrane [TsiGa]4, as a source of the monomer TsiGa for the preparation of a wide variety of organometallic compounds containing TsiGa as a ligand has been demonstrated (see, e.g., ). C(SiMe3)3 C(SiMe3)3 Ga Ga Ga Ga Ga C(SiMe3)3 (Me3Si)3C Ga Ga Ga C(SiMe3)3 C(SiMe3)3

(Me3Si)3C

Br

Li(THF)3

In (Me3Si)3C In Br In C(SiMe3)3 Br

69

71

The reaction of base-free TsiLi and GaX3 (X = Cl or I) at
78  C in a 1:1 ratio gives Li[TsiGaX3], but if 2 equiv. of TsiLi are used then a methylation occurs to give TsiGaMeCl . Reaction of GaCl3 with (EtMe2Si)3CLi gives [Li(THF)4][(EtMe2Si)3CGaCl3] in 49% yield. Both this species and the (Me3Si)3C analog can be reduced by magnesium to give the corresponding tetragallium tetrahedranes . The THF adduct, TsiGaMe2THF, can be isolated in 90% yield from the reaction between TsiLi2THF and Me2GaCl in THF. When the adduct is sublimed the THF is lost to give the solvent-free TsiGaMe2 , which can also be prepared in 58% yield from the reaction between base-free TsiLi and Me2GaCl . If a coordinating group is present in the trisilyllithium substituent, then solvent is excluded from the product; thus, reaction of 40 with GaCl3 generates the gallium analog of 61 in 58% yield . The reactions between InBr and trisilyllithium reagents as shown in Equation (12) afford oligomers of (RR1MeSi)3CIn, 70 . For RR1 = Me2, EtMe, and BunMe the compounds are tetrameric in benzene solution, while for the larger cases of RR1 = MePri and MePh the compounds are monomers in solution. For RR1 = Et2 there is a monomer–dimer equilibrium in solution. In the solid state when RR1 = Me2, EtMe, Et2, or MePri, the compounds are tetrameric, having a near perfect tetrahedral arrangement of indium atoms, similar to the tetrahedral gallium species described previously . In the reaction of TsiLi with InBr an unusual species 71 is also formed in 24% yield, which contains a chain of three indium atoms . The tetrahedrane [TsiIn]4 has been used as a convenient source of the monomer TsiIn for the preparation of a variety of organometallic compounds containing TsiIn (see, e.g., ). InBr + (RR1MeSi)3C-Li

Toluene, –40 °C

[(RR1MeSi)3CIn]n

70 R = Me, R1 = Me, 69%; R = Me, R1 = Et, 47% R = Me, R1 = Bun, 57%; R = Me, R1 = Pri, 64% R = Me, R1 = Ph, 66%; R = Et, R1 = Et, 56%

ð12Þ

The reaction of In(III) compounds with bulky lithium reagents has also continued to be of interest. Thus, the reaction of InBr3 with TsiLi in THF/Et2O gives a 60% yield of [Li(THF)4][TsiInBr3] and the reaction of TsiLi with Me2InCl in Et2O gives TsiInMe2 in 65% yield . The reaction of base-free TsiLi and InX3 (X = Cl, Br, or I) at
78  C in a 1:1 ratio gives Li[TsiInX3] but if 2 equiv. of TsiLi are used then a methylation occurs to give TsiInMeCl, and if 3 equiv. of TsiLi are used then two methylations occur to give TsiInMe2 together with the 1,3-disilacyclobutane [Me2Si
C(SiMe3)2]2 . If moisture is present in the reaction between TsiLi and Prn2InBr, an unusual hydroxide-bridged trimer, 72, is formed in 28% yield, presumably via hydrolysis of the initially formed TsiInPr2n . Some of the chemistry described above for gallium and indium can be extended to thallium. The reaction of TsiLi with the thallium(I) organometallic TlCp in a 1:1 ratio gives the deep red-violet TsiTl, which is tetrameric in the solid state having a slightly distorted tetrahedron of thallium atoms similar to that described above for the gallium and indium analogs .

Functions Containing at Least One Metalloid (Si, Ge, or B) (Me3Si)3C HO (Me3Si)3C In

397

OH In

H Prn O

C(SiMe3)3 In Prn

Prn 72

(e) Three Si and one group 14 metal functions. Compounds containing the Si3MC grouping where M = Sn or Pb are usually made by simple metathesis reactions between trisilyllithium reagents and metal halides. For example, reaction between SnX4 and TsiLi in Et2O at
78  C affords the expected TsiSnX3 compounds in excellent yields, 91% for X = Cl and 89% for X = Br . However, reaction between (Me3Si)3CLi and SnX4 (where X = Cl, Br, or I) in a 2:1 ratio in toluene solution gives (Me3Si)3C(PhCH2)SnX2 in 58%, 72%, and 76% yields respectively for X = Cl, Br, or I, apparently via a radical mechanism similar to that found in the germanium analog described in Section 6.13.1.1.2 . The related bulky reagent, (PhMe2Si)3CLi, reacts with SnCl4 in THF to give only a 25% yield of (PhMe2Si)3CSnCl3 along with (PhMe2Si)3CCl as the main product but it reacts more cleanly with Me2SnCl2 to give (PhMe2Si)3CSnMe2Cl, which reacts readily with EtOH to give the final product (PhMe2Si)3CSnMe2OEt in 76% yield . Related reagents that contain substituents capable of intramolecular coordination to the tin atom also undergo similar metathesis reactions. Thus reaction of 40 with SnCl4 gives (Me2NMe2Si)(Me3Si)2CSnCl3, which probably has intramolecular Sn
N coordination, in 78% yield , and treatment of (Me2NMe2Si)2(Me3Si)CLi with Me3SnCl gives (Me2NMe2Si)2(Me3Si)CSnMe3 (along with the precursor (Me2NMe2Si)2(Me3Si)CH) . Derivatization using Bu3SnCl of the organometallic reagent formed by metallation of 3 affords a derivative of 5 in which a Bu3Sn group has replaced the SiMe2R group . It is likely that a second metallation and further reaction with a tin halide would give a further range of compounds containing two Si3SnC substituted centers. Introduction of two tin atoms occurs in the reaction of the [Li(TMEDA)2] salt of 44 with Me2SnCl2 or the [Li(THF)4] salt of 44 with SnCl4 to afford [ClR2SnC(SiMe3)2SiMe2CH2]2 in 79% and 47% yields, respectively for R = Me and Cl . The Si3SnC grouping has also been prepared by using the reaction between a disilylstannyllithium reagent and a silyl chloride. Thus, (Me3Si)2(PhMe2Sn)CLi reacts with Me2SiCl2 to furnish (Me3Si)2(PhMe2Sn)CSiMe2Cl in 76% yield . Reactions of (Me3Si)2(PhMe2Sn)CLi (for its synthesis, see Section 6.13.1.3.1) with a range of other metal halides would, no doubt, allow convenient preparation of many new Si2SnMC groupings. The high degree of steric protection afforded by an (R3Si)3C substituent at a group 14 metal center has prompted investigation into the stabilization of M(II) species where M = Sn or Pb by such substituents. Reaction of (Me3Si)2(2-NC5H4Me2Si)CLi with SnCl2 or PbCl2 gives monomeric organotin- and organolead(II) chlorides in 74% and 47% yields, respectively, which have structures analogous to that of the related germanium compound 27 . The bis-methoxy species (MeOMe2Si)2Me3SiCLi reacts with SnCl2 to give (MeOMe2Si)2Me3SiCSnCl in 65% yield . The first structurally characterized organometallic ate complex of Sn(II), has a structure similar to that of the germanium analog, 28, and has been prepared in 60% yield from the reaction of (Me3Si)3CLi with Sn(SBun)2 . Treatment of the K(THF)2 salt of [CH2(SiMe2)(Me3Si)2C]2
2 (see Section 6.13.1.2.1(a)) with SnCl2 in Et2O at
78  C gives a mixture of dialkyl Sn(II) compounds 73 (M = Sn) and 74, both of which readily undergo oxidative addition reactions to give Sn(IV) compounds . Chlorobridged dimers 75 are formed from the reaction of (PhMe2Si)3CLi and MCl2 in THF . The lead species is a yellow-orange solid and is the first monoorganolead(II) derivative to be characterized. In contrast, if the smaller reagent TsiLi reacts with PbCl2 in THF then a chloro-bridged trimer 76 is produced in 85% yield . When the organolithium reagent (MeOMe2Si)(Me3Si)2CLi reacts with MCl2, where M = Sn or Pb, intramolecular coordination of the OMe group to the metal occurs to give the four-coordinate M(II) species 77 . Treatment of the [Li(TMEDA)2] salt of 44 with PbCl2 gives the Pb(II) organometallic species 73 (M = Pb) as dark blue crystals in 85% yield .

398

Functions Containing at Least One Metalloid (Si, Ge, or B) Me2Si (Me3Si)2C

SiMe2 C(SiMe3)2

CH2Me2Si(Me3Si)2CSnCl CH2Me2Si(Me3Si)2CSnCl

M

M (PhMe2Si)3C

74

73, M = Sn or Pb

(Me3Si)3C

Pb Cl

76

Cl

Pb Cl

C(SiMe3)3

Pb C(SiMe3)3

Cl C(SiMe2Ph)3 M Cl

75, M = Sn or Pb SiMe3 Me Me3Si Cl O C SiMe2 M M Me2Si Cl C O SiMe3 Me Me3Si 77, M = Sn, 93%; M = Pb, 60%

(f) Three Si and one transition metal functions. The reaction of lithium reagent 39 with CrCl2 gives a 40% yield of 78 having a square-planar geometry at Cr, together with a small amount of 79 . Reaction of TsiLi2THF with CrCl2 is reported to give Tsi2Cr, but no details have been given .

N Me2Si SiMe3 Me3Si C Cr C SiMe3 Me3Si SiMe2 N

N Me2Si Me3Si C Cr Cl SiMe3 Me3Si Cl Cr C SiMe3 N SiMe2

78

79

Reaction of the lithium reagent 39 with MnCl2 gives the manganese complex 80 in 41% yield . Similarly, the lithium reagent 40 reacts with 1 equiv. of MnCl2 to give a 95% yield of 81 X = Cl, and with 0.5 equiv. of MnCl2 to give [(Me2NMe2Si)(Me3Si)2C]2Mn in 72% yield together with a small amount of the Mn(III) complex 81 X = O (presumably formed via oxidation by adventitious air) . Reaction of the related reagent containing a chelating methoxy group (see Table 2) with MnCl2 gives 82 in 63% yield while the use of the chelated dialkyllithium reagent 44 affords the chloride-bridged, high-spin manganese complex 83 in 60% yield .

N Me2Si Me3Si C Mn Cl Me3Si Cl

Li(THF)3

80 THF Me (Me3Si)2 C Cl O Me2Si Mn Mn SiMe2 O Cl C (SiMe3)2 Me THF 82

Me2Si NMe2 Me3Si C Mn X SiMe3 Me3Si X Mn C SiMe3 Me2N SiMe2 81, X = Cl, X = O Me2Si (Me3Si)2C

SiMe2 C(SiMe3)2 Mn Cl Li(THF)3 83

Reaction of base-free TsiLi with FeCl3 leads to reduction and formation of the Fe(II) compound Tsi2Fe in 68% yield . If coordinated THF is present in the lithium reagent, TsiLi2THF, then reaction with FeCl2 at
35  C in THF solution also occurs to give red blocks of Tsi2Fe in 44% yield .

399

Functions Containing at Least One Metalloid (Si, Ge, or B)

Reaction of the lithium reagent 39 with CoBr2 gives the halide-bridged ate complex 84 in 56% yield . Similarly, lithium reagent 40 containing a dimethylamino substituent capable of acting as a ligand, reacts with CoBr2 to give 85 in 50% yield . The simple diorganocobalt compound Tsi2Co has been reported to be formed as dark-green, plate-like crystals from the reaction between CoCl2 and TsiLi2THF but no spectroscopic details are available .

N Me2Si Me3Si C Co Br Me3Si Br Li(THF)2

Me2Si NMe2 Me3Si C Co Br SiMe3 Me3Si Br Co C SiMe3 Me2N SiMe2

84

85

The first
-bonded organonickel(I) compound 86 is obtained in 30% yield from the reaction shown in Scheme 4. Trace amounts of hydroxide present in the starting material are thought to be responsible for the formation of complex 87 as a minor by-product. In contrast, reaction of [PdCl2(PPh3)2] gave the chloro-bridged dimer 88 as a pale yellow solid in 53% yield .

2 [PdCl2(PPh3)2]

N Me2Si Me3Si C Li THF Me3Si

[NiCl2(PPh3)2] THF, –78 °C trace H2O

THF, –78 °C

N

Me3Si

SiMe3 C

SiMe2 Cl Pd Pd Cl C N SiMe3 Me3Si

Me2Si

N Me2Si Me3Si C Ni PPh3 Me3Si 86

88

Me2 SiMe 3 Si C N O SiMe2 Ni Ni O N Me2Si C Si Me3Si Me2 87

Scheme 4

Reaction of 39 with CuI or AuClSMe2 gives dimeric products 89 M = Cu or Au in 62% and 37% yields, respectively . Me2 (Me3Si)2C Si M N M N Si C(SiMe3)2 Me2

89, M = Cu or Au

The reactions between group I metal derivatives of trisilylmethanes and CuCN can give a variety of products. Thus, treatment of CuCN with (PhMe2Si)3CM (M = Li or Na) in THF solution affords the monomeric species (PhMe2Si)3CCuCNM(THF)3 which, when crystallized from toluene, gives the dimeric species 90 . Similar dimers, 91 and 92, are formed, in 65% and 41% yield, respectively, directly from reactions with (RMe2Si)(Me3Si)2CLi (R = Me or NMe2) while (MeOMe2Si)2(Me3Si)CLi gives 93 . Crystallization of the product formed from the potassium reagent (PhMe2Si)3CK and CuCN gives the tetramer 94 in 43% yield .

400

Functions Containing at Least One Metalloid (Si, Ge, or B) SiMe3

THF Li

THF

THF Li RCu CN NC CuR Li THF THF

Cu

CN

SiMe2

OMe

MeO

Me2Si Me2Si

90, R = (PhMe2Si)3C 91, R = (Me3Si)3C 92, R = (Me2NMe2)(Me3Si)2C

C SiMe2

MeO OMe C

Cu

CN

Me3Si

Li THF

93

K RCu

C

N

K C

RCu

N

N

K

K

C

CuR

94, R = (PhMe2Si)3C

N C CuR

(g) Three Si and one lanthanide or actinide functions. The first structurally characterized
-bonded organosamarium(II) complex [Sm{C(SiMe3)2(SiMe2OMe)}2THF] was obtained from the reaction between K{C(SiMe3)2(SiMe2OMe)} and [SmI2(THF)2]. The compound is isolated as deep green-black, air-sensitive crystals in 71% yield and should inspire further work into alkyl, rather than the more well-known cyclopentadienyl, derivatives of samarium . Reaction of a range of alkylpotassium species with YbI2 (Equation (13)) in benzene solution gives simple, monomeric dialkylytterbium compounds 95 including the solvent-free dialkyl lanthanide compound Tsi2Yb as an orange solid in 85% yield which, despite the steric encumbrance of the Tsi groups, is bent at Yb (C
Yb
C angle 137 ) and can act as a polymerization catalyst for methylmethacrylate . A similar metathetical reaction occurs between TsiK and EuI2 to give the bent species Tsi2Eu in 65% yield . Grignard-like complexes [RYbIEt2O]2, 96, are formed from the reaction between RI and elemental Yb in Et2O (Equation (14)) . Reaction of the dipotassium compound 48 with YbI2 in benzene solution affords 97 in 45% yield . In contrast to the reactions carried out in benzene as a solvent, reaction between TsiK and YbI2 in Et2O in either a 2:1 or a 1:1 ratio gives the centrosymmetric dimer 98 as orange-red crystals in 63% yield. It is not clear how the EtO
group is generated, but possibly by the Lewis acid character of initially formed Tsi2Yb or TsiK cleaving the solvent . YbI2 +

2(Me3Si)2(Me2RSi)CK

C6H6

[(Me3Si)2(Me2RSi)C]2Yb + 2KI 95, R = Me, 85% R = CH2=CH, 80% R = EtOCH2CH2, 70%

(Me3Si)2(Me2RSi)CI + Ybpowder

Et2O

Et2O

Yb

(RMe2Si)(Me3Si)2C

C(SiMe3)2(SiMe2R) I Yb I OEt2

96, R = Me R = OMe, 65%

Me2Si (Me3Si)2C

SiMe2 C(SiMe3)2 Yb 97

Et O C(SiMe3)3 Yb Yb O (Me3Si)3C OEt2 Et Et2O

98

No trisilylmethyl derivatives of the actinide elements seem to have been prepared.

ð13Þ

ð14Þ

401

Functions Containing at Least One Metalloid (Si, Ge, or B) (ii) Three Ge and one metal functions

As has been seen in sections above there is a general lack of compounds containing several germanium atoms attached to the same carbon and there do not appear to be any compounds containing the Ge3MC grouping known. Such compounds should be readily available via the routes used to prepare the many analogous Si3MC containing functions as described above.

(iii) Three B functions As has been described above, there are few compounds containing several boron atoms attached to carbon apart from carboranes and other compounds with multicenter bonding. See reference for early work in this field.

6.13.1.2.2

Other mixed metalloid functions

(i) Two Si, one Ge, and one metal functions Treatment of XMe2GeCBr(SiMe3)2 with PhLi (for X = Br) or Bun (for X = OPh) at low temperature gives XMe2GeCLi(SiMe3)2 species which, on warming, eliminates LiX to give the unsaturated Me2Ge¼C(SiMe3)2 .

(ii) Two Si, one B, and one metal functions The products obtained from the reaction between boriranylideboranes and [CoCp(C2H4)2] depend on the substituents at boron. For R = duryl (2,3,5,6-Me4C6H) or mesityl the dinuclear metal complexes 99 are formed (in 46% and 19% yields, respectively) but for R = But the mononuclear complex 100 is formed (Scheme 5) in 11% yield . R

R

B B

Me3Si

C

C

Me3Si 2[CoCp(C2H4)2]

2[CoCp(C2H4)2] R = mesityl or duryl Co Me3Si Me3Si

C

R = But

R C B

B

Co Me3Si

Men

Me3Si

Co 99

C

B

But

B But 100

Scheme 5

(iii) One Si, one Ge, one B, and one metal functions. Also two Ge, one Si, and one metal functions. Also two Ge, one B, and one metal functions. Also Two B, one Si, and one metal functions. Also two B, one Ge, and one metal functions Very few examples of compounds containing these functions seem to have been prepared. Compounds containing such functions should, however, be available from synthetic routes described above in this section. In particular, such functions should be available from the reactions between suitably substituted lithium reagents and appropriate metal halides.

402

Functions Containing at Least One Metalloid (Si, Ge, or B)

As would be expected from the ready metallations of trisilylmethane derivatives the digermylsilylmethane (Me3Ge)2(FBut2Si)CH reacts with MeLi in THF/Et2O to give (Me3Ge)2(FBuFBut2Si)CLi, which, when treated with Me3SnCl, affords (Me3Ge)2(FBut2Si)CSnMe3 in 51% yield .

6.13.1.3 6.13.1.3.1

Methanes Bearing Two Metalloid and Two Metal Functions Two Si and two metal functions

Metallation of BrMe2SnCBr(SiMe3)2 by PhLi affords BrMe2SnCLi(SiMe3)2 which, when warmed, eliminates LiBr to give first a stannene and then a cyclic dimer, 101, as shown in Scheme 6 . A related bulky methyllithium derivative (Me3Si)2(PhMe2Sn)CLi was readily prepared via Sn
C bond cleavage of (Me3Si)2(PhMe2Sn)2C by MeLi in THF/Et2O .

Me2Sn C(SiMe3)2 + PhLi Br Br

Et2O

Me2Sn C(SiMe3)2 Br Li

low temp.

Warm

Me2Sn C(SiMe3)2

–LiBr x2 Me2Sn C(SiMe3)2 (Me3Si)2C SnMe2 101

Scheme 6

Attempts have been made to prepare (Me3Si)2CLi2 by the pyrolysis of either the ate complex [Li(THF)4][Tsi2Li] or the solvent-free [TsiLi]2 (a method that works in the synthesis of (Me3Si)2SiLi2 from (Me3Si)3SiLi) but they fail and give instead oligomeric products .

6.13.1.3.2

Two Ge and two metal functions

There do not appear to be any compounds containing this function but they could, doubtless, be prepared in similar ways to the analogous Si2M2C-containing species described above in Section 6.13.1.3.1.

6.13.1.3.3

Two B and two metal functions

Compounds containing this grouping are relatively rare (see for early work in the area). A range of diboraallenes, 102, containing a four-coordinate planar carbon can be prepared according to Equation (15) from the anions 103 . Synthetic approaches to planar carbon atoms have often involved the preparation of compounds containing carbons heavily substituted by metalloids or metals and this work has been reviewed in .

R1

– B C B R1

+

2 R2Li

–(Me3Si)2CHLi

(Me3Si)2CH 103

R1 R2

R1 = R2 = mesityl R1 = R2 = 2,3,5,6-Me4C6H R1 = R2 = 2,6,-Me24-ButC6H2 R1 = mesityl, R2 = But

OEt2 Li – R1 – B C B R2 Li OEt2 102

ð15Þ

Functions Containing at Least One Metalloid (Si, Ge, or B) 6.13.1.3.4

403

Other combinations of two metalloids and two metal functions

There are very few compounds known containing mixed metalloids and two metal functions. They should, however, be available by the routes described above for related compounds containing two of the same metalloid. One notable example of this type of compound is racemic (Me3Pb)(Me3Sn)(Me3Ge)(Me3Si)C, a molecule containing all the elements of group 14 connected together, which can be obtained from a series of metathesis reactions .

6.13.1.4

Methanes Bearing One Metalloid and Three Metal Functions

6.13.1.4.1

One Si and three metal functions

Relatively few new compounds of this type have been prepared since those described in . The bulky dialkyltitanium complex 104 reacts with AlMe3 (Equation (16)) to give the four-coordinate carbide complex 105 in 78% yield .

Cp Me3 Si

Ti

N

PPr3i

SiMe3

PPr3i 3AlMe3 –3CH4

Cp Me

104

6.13.1.4.2

Ti

N AlMe2 C

+ AlMe2CH2SiMe3

ð16Þ

Al SiMe3 Me2 105

One Ge and three metal functions

No new compounds containing this grouping seem to have been prepared since those described in .

6.13.1.4.3

One B and three metal functions

There seem to be few, if any, compounds of this type known. It may be possible to prepare such species by the reaction of a methylidyne cluster with a borane, R2BH, in a manner similar to that used in the preparation of silyl-substituted alkylidyne complexes.

6.13.2 6.13.2.1

METHANES BEARING FOUR METAL FUNCTIONS Methanes Bearing Four Similar Metals

A slightly modified method for the preparation of (Me3Sn)4C from CCl4, Li, and Me3SnCl has been reported together with new spectroscopic data . This compound does not seem to have been of use in synthesis but has been the subject of several detailed structural studies (see, e.g., ). A method for obtaining very pure Hofmann’s base, [CHg4O(OH)2OH2]n, has been described . The pure base can be used in the preparation of C(HgNO3)4 and C(HgSO4)2(HgOH2)2.

6.13.2.2

Methanes Bearing Three Similar and One Different Metal Functions

Treatment of phosphinimide complexes 106 with excess AlMe3 leads to multiple C
H bond activation and formation of the carbide complexes 107 in good yield (Equation (17)) . (For the products from the analogous reaction with bulky alkyl substituents at Ti see Section 6.13.1.4.1, and for their behavior in solution see Section 6.13.3.)

404

Functions Containing at Least One Metalloid (Si, Ge, or B) PR3 PR3 N Cp1 Ti Me Me

Cp1

3AlMe3

AlMe2

ð17Þ

C

Al AlMe2 Me2

1 i 106, Cp = Cp; R = Cy or Pr Cp1 = indenyl; R = Pri

6.13.2.3

Ti

Me

–3CH4

N

107

Methanes Bearing Two Similar and Two Different Metal Functions

Compounds containing this type of grouping seem to be very rare although carbons coordinated by different metals may well occur in metal carbides, these are outside the scope of this chapter.

6.13.2.4

Methanes Bearing Four Different Metal Functions

Although there are a potential 135 751 different combinations (and their optical isomers) of 43 different metals at a tetrahedral carbon center, very few seem to have been prepared. A comprehensive search of the literature for such a large number of functional groups is clearly very difficult to carry out and it is quite possible that many such groupings have been missed in compiling this article. It is hoped that any omissions of such groupings will not be serious for the organic chemist.

6.13.3

METHANES BEARING MORE THAN FOUR METALLOID OR METAL FUNCTIONS

Polyhedral metallacarboranes in which carbon is bonded to more than four metalloid or metal centers via multicenter interactions are numerous but beyond the scope of this article. Reviews of metallacarborane chemistry can be found in . Variable temperature NMR studies show that the four-coordinate carbide complexes, 107 (see Section 6.13.2.2), are in equilibrium (Equation (18)) with five-coordinate complexes 108 in the presence of AlMe3 . Cp

PR3 Cp

Ti

Me

N AlMe2

C Al AlMe2 Me2

AlMe3 –AlMe3

Me Me2Al

PR3 Me2 N Al

Ti C

Me

ð18Þ

Al Me2

107 R = Pri or Ph

AlMe2

108

ACKNOWLEDGMENTS This chapter is dedicated to Professor C. Eaborn, FRS, who died in February 2004. Much of the chemistry described above was initiated in the Eaborn group and the versatility of reagents, such as (Me3Si)3CLi, that have now become popular across a wide range of organometallic chemistry was demonstrated first in the research laboratories at Sussex University.

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Functions Containing at Least One Metalloid (Si, Ge, or B) 2001JA994 2001JCS(D)1541 2001JCS(D)3397 2001JOM(620)127 2001JOM(631)76 2001JOM(640)29 2001MI(162)225 2001OM1175 2001OM1223 2001OM2047 2001ZAAC(627)715 2002AG(E)1365 2002AG(E)3829 2002CCC728 2002CCC869 2002CCR(231)23 2002CCR(232)173 2002JCS(D)2467 2002JCS(D)3971 2002JCS(D)3975 2002JOM(647)128 2002JOM(649)121 2002OM2183 2002OM2430 2002OM4005 2002USP00334829 2002ZAAC(628)1963 2003AG(E)669 2003AG(E)671 2003ICA(345)359 2003JA7534 2003OM2505 2003OM2705 2003T10409 2004JOM(689)1238 2004JOM(689)1718

407

Z.-X. Wang, P. v. R. Schleyer, J. Am. Chem. Soc. 2001, 123, 994. C. Eaborn, J. D. Smith, J. Chem. Soc., Dalton Trans. 2001, 1541. C. Eaborn, J. Chem. Soc., Dalton Trans. 2001, 3397. E. J. Hawrelak, D. Sata, F. T. Lapido, J. Organomet. Chem. 2001, 620, 127. S. S. Al-Juaid, A. G. Avent, C. Eaborn, S. M. El-Hamruni, S. A. Hawkes, M. S. Hill, M. Hopman, P. B. Hitchcock, J. D. Smith, J. Organomet. Chem. 2001, 631, 76. C. Eaborn, A. Kowalewska, J. D. Smith, W. A. Stan´czyk, J. Organomet. Chem. 2001, 640, 29. M. Schormann, K. S. Klimek, H. Hatop, S. P. Varkey, H. W. Roesky, C. Lehman, C. Ro¨pken, R. Herbst-Irmer, M. Noltemeyer, J. Solid State Chem. 2001, 162, 225. J. E. Kickham, F. Gue´rin, J. C. Stewart, E. Urbanska, D. W. Stephan, Organometallics 2001, 20, 1175. S. S. Al-Juaid, A. G. Avent, C. Eaborn, M. S. Hill, P. B. Hitchcock, D. J. Patel, J. D. Smith, Organometallics 2001, 20, 1223. K. S. Klimek, J. Prust, H. W. Roesky, M. Noltemeyer, H.-G. Schmidt, Organometallics 2001, 20, 2047. T. Viefhaus, W. Schwarz, K. Hubler, K. Locke, J. Weidlein, Z. Anorg. Allg. Chem. 2001, 627, 715. J. Janssen, J. Magull, H. W. Roesky, Angew. Chem., Int. Ed. Engl. 2002, 41, 1365. W. W. du Mont, T. Gust, E. Seppa¨la¨, C. Wismach, P. G. Jones, L. Ernst, J. Grunenberg, H. C. Marsmann, Angew. Chem., Int. Ed. Engl. 2002, 41, 3829. R. N. Grimes, Coll. Czech. Chem. 2002, 67, 728. A. Franken, C. A. Kilner, M. Thornton-Pett, J. D. Kennedy, Coll. Czech. Chem. 2002, 67, 869. Z. Xie, Coord. Chem. Rev. 2002, 231, 23. J. F. Valliant, K. J. Guenther, A. S. King, P. Morel, P. Schaffer, O. O. Sogbein, K. A. Stephenson, Coord. Chem. Rev. 2002, 232, 173. C. Eaborn, M. S. Hill, P. B. Hitchcock, J. D. Smith, J. Chem. Soc., Dalton Trans. 2002, 2467. A. G. Avent, C. Eaborn, I. B. Gorrell, P. B. Hitchcock, J. D. Smith, J. Chem. Soc., Dalton Trans. 2002, 3971. C. Eaborn, S. M. El-Hamruni, M. S. Hill, P. B. Hitchcock, J. D. Smith, J. Chem. Soc., Dalton Trans. 2002, 3975. H. Yasuda, J. Organomet. Chem. 2002, 647, 128. S. S. Al-Juaid, C. Eaborn, S. M. El-Hamruni, P. B. Hitchcock, J. D. Smith, S. E. So¨zerli, J. Organomet. Chem. 2002, 649, 121. A. Asadi, A. G. Avent, C. Eaborn, M. S. Hill, P. B. Hitchcock, M. M. Meehan, J. D. Smith, Organometallics 2002, 21, 2183. A. Asadi, C. Eaborn, M. S. Hill, P. B. Hitchcock, M. M. Meehan, J. D. Smith, Organometallics 2002, 21, 2430. I. V. Borisova, C. Eaborn, M. S. Hill, V. N. Khrustalev, M. G. Kuznetzova, J. D. Smith, Y. A. Ustynyuk, V. V. Lunin, N. N. Zemlyansky, Organometallics 2002, 21, 4005. Hall, K.; Murphy, V.; Lapointe, A. M.; Van Beek, J. A. M.; Diamond, G. M. U.S. Patent 200200334829; CAN 136, 263 599. W. Uhl, F. Schmock, G. Gieseler, Z, Anorg. Allg. Chem. 2002, 628, 1963. Y. Sahin, C. Prasang, P. Amseis, M. Hofmann, G. Geiseler, W. Massa, A. Berndt, Angew. Chem., Int. Ed. Engl. 2003, 42, 669. Y. Sahin, C. Prasang, M. Hofmann, G. Subramaniam, G. Geiseler, W. Massa, A. Berndt, Angew. Chem., Int. Ed. Engl. 2003, 42, 671. A. M. LaPointe, Inorg. Chim. Acta 2003, 345, 359. K. Izod, S. T. Liddle, W. Clegg, J. Am. Chem. Soc. 2003, 125, 7534. F. Antolini, P. B. Hitchcock, M. F. Lappert, X.-H. Wei, Organometallics 2003, 22, 2505. C. Gemel, T. Steinke, D. Weiss, M. Cokoja, M. Winter, R. A. Fischer, Organometallics 2003, 22, 2705. G. Qi, Y. Nitto, A. Saiki, T. Tomohiro, Y. Nakayama, H. Yasuda, Tetrahedron 2003, 59, 10409. A. Asadi, A. G. Avent, M. P. Coles, C. Eaborn, P. B. Hitchcock, J. D. Smith, J. Organomet. Chem. 2004, 689, 1238. D. Azarifar, M. P. Coles, S. M. Al-Hamruni, C. Eaborn, P. B. Hitchcock, J. D. Smith, J. Organomet. Chem. 2004, 689, 1718.

408

Functions Containing at Least One Metalloid (Si, Ge, or B) Biographical sketch

Paul D. Lickiss was born in Kent, the Garden of England, studied at The University of Sussex, where he obtained a B.Sc. degree in 1980 and his D.Phil. in 1983 under the supervision of Professor C. Eaborn, FRS. After staying at the University of Toronto with Professor Adrian Brook from 1983 to 1984, he returned to Sussex and took up a position as a Royal Society 1983 University Research Fellow in 1985. In 1989 he resigned his Fellowship to take up a position as a lecturer in the University of Salford where he stayed for four years. From the 1990s, he has been a Lecturer, Senior Lecturer, and now Reader in organometallic chemistry in the Synthesis Section in the Chemistry Department at Imperial College, London. His research interests are mainly in the field of organosilicon chemistry, particularly the synthesis of low-coordinate compounds such as silyl cations and the use of bulky groups to stabilize unusual compounds. He is also interested in the synthesis and uses of organosilanols, especially those containing several Si–OH groups. The use of ultrasound for synthesis is also actively pursued.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 381–408

6.14 Functions Containing a Carbonyl Group and at Least One Halogen R. MURUGAN and S. V. YARLAGADDA Reilly Industries Inc., Indianapolis, IN, USA 6.14.1 INTRODUCTION 6.14.2 CARBONYL HALIDES WITH TWO SIMILAR HALOGENS 6.14.2.1 Carbonic Difluoride 6.14.2.2 Carbonic Dichloride 6.14.2.2.1 Preparation of phosgene 6.14.2.2.2 Phosgene alternatives 6.14.2.3 Carbonic Dibromide 6.14.2.4 Carbonic Diiodide 6.14.3 CARBONYL HALIDES WITH TWO DISSIMILAR HALOGENS 6.14.3.1 One Fluorine and Chlorine, Bromine, or Iodine 6.14.3.1.1 Carbonic chloride fluoride 6.14.3.1.2 Carbonic bromide fluoride 6.14.3.1.3 Carbonic fluoride iodide 6.14.3.2 One Chlorine and Bromine or Iodine 6.14.3.2.1 Carbonic bromide chloride 6.14.3.2.2 Carbonic chloride iodide 6.14.3.3 One Bromine and Iodine 6.14.3.3.1 Carbonic bromide iodide 6.14.4 CARBONYL HALIDES WITH ONE HALOGEN AND ONE OTHER HETEROATOM 6.14.4.1 One Halogen and One Oxygen 6.14.4.1.1 Fluoroformate esters 6.14.4.1.2 Chloroformate esters 6.14.4.1.3 Bromoformate esters 6.14.4.1.4 Iodoformate esters 6.14.4.2 One Halogen and One Sulfur 6.14.4.2.1 Fluorothiolformate esters 6.14.4.2.2 Chlorothiolformate esters 6.14.4.2.3 Bromothiolformate esters 6.14.4.2.4 Iodothiolformate esters 6.14.4.3 One Halogen and One Nitrogen 6.14.4.3.1 Carbamoyl fluorides 6.14.4.3.2 Carbamoyl chlorides 6.14.4.3.3 Carbamoyl bromides 6.14.4.3.4 Carbamoyl iodides 6.14.4.4 One Halogen and One Phosphorus 6.14.4.4.1 Chlorocarbonyl derivatives of phosphorus(III) 6.14.4.4.2 Chlorocarbonyl derivatives of phosphorus(V) 6.14.4.5 One Halogen and One Arsenic, Antimony, or Bismuth 6.14.4.6 One Halogen and One Metalloid (Boron, Silicon, or Germanium) 6.14.4.7 One Halogen and One Metal 6.14.4.7.1 Halocarbonyl complexes of first transition metal series (iron and chromium) 6.14.4.7.2 Halocarbonyl complexes of second transition metal series (ruthenium and rhodium) 6.14.4.7.3 Halocarbonyl complexes of third transition metal series (rhenium and iridium)

409

410 410 410 411 411 411 412 412 413 413 413 413 414 414 414 414 414 414 414 414 415 415 419 419 419 419 420 420 420 420 421 421 422 422 422 422 423 423 423 424 424 424 424

410 6.14.1

Functions Containing a Carbonyl Group and at Least One Halogen INTRODUCTION

The literature search was done using the general term carbonyl halides and other specific compounds such as carbonyl difluoride, phosgene, chloroformates, etc., discussed by name in this chapter. As observed by the authors, of COFGT (1995) , the present authors observed more literature on those compounds, when the halogen is chlorine. For example, there are more references on carbonyl dichloride than those on carbonyl difluoride, carbonyl dibromide, and carbonyl diiodide combined. Similarly in the case of halo formate derivatives there are more references on chloro formates than those on, fluoro-, bromo-, or iodo-formates. The arrangement of sections and subsections is similar to that of COFGT (1995) , except some sections are not repeated as not much has changed between then and the end of 2003. For example, the section on toxicity and handling of phosgene is not repeated here. In the decade up to 2003, the trend has been towards the ‘‘green chemistry’’ concept of alternative synthetic approaches for the titled functional groups that would replace toxic substances like carbon monoxide and phosgene with other relatively less/nontoxic chemicals like carbon dioxide.

6.14.2

CARBONYL HALIDES WITH TWO SIMILAR HALOGENS

The general preparations reported in on these carbonyl difluoride, dichloride, dibromide, and diiodide are summarized in Scheme 1. There are three general synthetic routes for these compounds. One of the methods is by halogen exchange reaction on carbonyl chloride or phosgene using a halide source. The other two methods start from carbon monoxide and halogen (carbon monoxide insertion into halogens works well for carbonyl difluoride and dichloride), and oxidation of a perhalogenated organic compound with an oxygen oxidant (works well for carbonyl dibromide). X2

CO

COX2

Oxidant

CX4

2X– COCl2

Scheme 1

6.14.2.1

Carbonic Difluoride

A novel approach to making carbonyl difluoride has been to react carbon dioxide and fluorine gas (Equation (1)). This method does not use toxic compounds such as phosgene and carbon monoxide. Carbon dioxide and fluorine are allowed to react with each other in the gaseous state, to produce carbonyl difluoride, at a preferred temperature range of 150–250
C with a mole ratio of 0.5:2, and near atmospheric pressure in a fluorine resistant metal, such as stainless steel, under anhydrous conditions . CO2

+

F2

COF2

ð1Þ

Carbonyl difluoride has been used in the synthesis of fluorinated methyl ethers of the formula R2CHOCF2A where A is Cl or F, and each R is H, (CF2)nCl, (CF2)nF, or (CF2)nH (where n = 1–10). Dry etching of high-melting-point metals has been achieved by using carbonyl compounds, specifically that of carbonyl difluoride . This process has been useful for forming electrodes, circuits, etc.

Functions Containing a Carbonyl Group and at Least One Halogen 6.14.2.2

411

Carbonic Dichloride

Carbonic dichloride or carbonyl dichloride or phosgene is the most important of all the functional compounds mentioned in this chapter. It is made commercially in large quantities and almost all the other functional groups mentioned in this chapter could be obtained by chemical transformations on phosgene. Phosgene is also a highly toxic and very reactive compound. It is an industrially important compound, as it is used in the preparation of polyurethanes and polycarbonates. Hence, it is the most studied of all the functional groups mentioned in this chapter. In the early 2000s, there is an awareness that phosgene should be replaced by other less toxic chemicals in the synthesis of polyurethanes and polycarbonates.

6.14.2.2.1

Preparation of phosgene

In general, phosgene has been prepared in three ways: the classical synthesis of insertion of carbon monoxide to chlorine; the chemical as well as photochemical oxidation of perchlorinated compounds; and the decomposition of other phosgene derivatives such as chloroformates and carbonates which are also used as phosgene alternatives. All these methods have been discussed in COFGT (1995) . Phosgene is also produced as one of the products in the photocatalytic degradation of perhalogenated hydrocarbons on porous titanium oxide . A report on the synthesis of phosgene from triphosgene or bis(trichloromethyl)carbonate, along with the comparison of the reactivity of phosgene with that of diphosgene and triphosgene with methanol, has been published . Phosgene can be manufactured from diphosgene and triphosgene using deactivated amines as the catalysts. The amine catalysts are selected from poly(2-vinylpyridine), phenanthridine, phthalocyanines, and metallophthalocyanines free and on a polymer support, and poly(N,N-dimethylaminomethylstyrene) . There are a few reports of carbon labeled phosgene synthesis, which were also discussed in COFGT (1995) . Even in the preparation of 11C-labeled phosgene to make 11C-labeled ureas and isocyanates, alternatives like 11C-labeled carbon dioxide have been used . Another example of the use of 11C-carbon monoxide in place of labeled phosgene is in the preparation of 11C-carbamoyl compounds using selenium . 11 C-Phosgene, a useful precursor for labeling several radiopharmaceuticals, is generally made by catalytic oxidation of 11C-carbon tetrachloride over iron granules, although in low yields or with poor reproducibility. Chlorination of 11C-methane followed by reaction with a stream of 98:2 nitrogen/oxygen over iron has provided 11C-phosgene . The yield of 11C-phosgene was significantly increased by using iron oxide along with iron granules . A simple review of the history, preparation, and uses of phosgene was done by Senet . A modified production of phosgene from carbon monoxide and chlorine has been patented. This patent claims the use of a metal halide catalyst preferably selected from group III metals like aluminum and gallium . An improved method for the preparation of phosgene in the laboratory has been reported. In this approach phosgene was prepared by addition of 95–98% sulfuric acid to a mixture of phosphorus pentoxide and carbon tetrachloride . An interesting way to address the toxicity and safety issues associated with phosgene is the use of a microfabricated reactor for its manufacture. This is an example of the potential for safe on-site/on-demand production of a hazardous compound, in this case phosgene. Complete conversion of chlorine is observed for a 1:1 feed at 8 cc/min, which gives a projected productivity of approximately 100 kg/year from a 10-channel microreactor, with the opportunity to produce significant quantities by operating many reactors in parallel .

6.14.2.2.2

Phosgene alternatives

Because of the toxicity and the high reactivity of phosgene, many alternatives have been made and used as phosgene equivalents. Interestingly, most of them are made from phosgene but are easier to handle than phosgene itself. The most common phosgene alternatives mentioned in COFGT (1995) are summarized in Scheme 2.

412

Functions Containing a Carbonyl Group and at Least One Halogen N O

N N

Imidazole

COCl2

Methanol

Phosgene

CH3OCOCl

Methanol CH3OCOOCH3 Cl2

Cl2

N CCl3OCOCl

CCl3OCOOCCl3

Diphosgene

Triphosgene

Scheme 2

Ureas have been traditionally synthesized by methodologies mainly based on the use of dangerous reagents such as phosgene and isocyanates. However, in the late 1990s and early 2000s, these reagents have been increasingly substituted by cleaner and inherently safer compounds, referred to as phosgene substitutes, such as bis(4-nitrophenyl)carbonate, triphosgene, di-t-butyl-dicarbonate, 1,1-carbonylbisimidazole, 1,1-carbonylbisbenzotriazole, S,S-dimethyl dithiocarbonate, and trihaloacetyl chlorides. These safer reagents could be stored and handled without special precautions . Phosgene has been replaced with carbon dioxide in the synthesis of alkyl carbonates. Mixed or symmetrical dialkyl carbonates were generated in high yields (53–97%) from alcohols, carbon dioxide, and alkyl chlorides in apolar aprotic solvents using guanidine bases under mild conditions .

(i) Prepared from phosgene The common phosgene alternatives are usually made from phosgene, replacing either one or both of the chlorine atoms with a leaving group, and thus making the whole compound more stable and easier to handle. There are also reviews on the use of these phosgene alternatives. For example, the use of bis(trichloromethyl)carbonate or triphosgene in organic synthesis as a substitute for phosgene is well reviewed . The preparation of N,N0 -carbonyldiimidazole has been reported, starting from imidazole and phosgene. Reaction of imidazole with phosgene in toluene in the presence of tributylamine gave 76% yield of N,N0 -carbonyldiimidazole .

6.14.2.3

Carbonic Dibromide

Carbon monoxide and bromine are reacted over activated carbon to give carbonyl dibromide (Equation (2)). Like phosgene, carbonyl dibromide is also used in the synthesis of compounds such as diaryl carbonates . In the application on the use of carbonyl dibromide in the preparation of diaryl carbonates, aluminum trifluoride has been used as the catalyst . Carbonyl dibromide is also used in the synthesis of metal bromides and their bromide oxides . This reaction of carbonyl bromide with metal oxides is further discussed in Section 6.14.4.7 on the halocarbonyl metal compounds. Activated “C” CO

6.14.2.4

+

Br2

COBr2

ð2Þ

Carbonic Diiodide

This compound was not reported in COFGT (1995) and many attempts to make this compound have failed. It was suggested that this may be due to its poor stability. However, it has been found that heating carbon tetraiodide in a stream of oxygen results in the formation of carbonyl diiodide, and this has been confirmed from its infrared (IR) spectrum (Equation (3)) . Carbonyl diiodide, which is similar to carbonyl difluoride, has

Functions Containing a Carbonyl Group and at Least One Halogen

413

been used in the decontamination of metal surfaces that are contaminated by metal oxides of U, Pu, Np, Tc, etc. The metal oxides are converted into their iodides or carbonyl complexes, which are volatile and hence removed by vacuum . CI4

6.14.3

O2

+

ð3Þ

COI2

CARBONYL HALIDES WITH TWO DISSIMILAR HALOGENS

The general syntheses of these compounds mentioned in COFGT (1995) are summarized in Scheme 3 . The two major approaches are: the insertion of carbon monoxide with the mixed halogen compound, and halogen exchange with a halide ion source on a carbonyl dihalide with a different halogen. X1X2

X1–

COX1X2

CO

COCl2

–Cl–

Scheme 3

6.14.3.1 6.14.3.1.1

One Fluorine and Chlorine, Bromine, or Iodine Carbonic chloride fluoride

An improved method for the synthesis of carbonyl chloride fluoride under mild conditions has been reported. Pure carbonyl chloride fluoride can be isolated in essentially quantitative yield from the decomposition of the oxygen-bridged COCl2SbF5 donor–acceptor adduct at room temperature (rt) in a dynamic vacuum (Equation (4)). These adducts along with that of carbonyl chloride fluoride and penta fluoro compounds have been studied using vibrational spectroscopy, nuclear magnetic resonance (NMR), mass spectra, and theoretical calculations . COCI2.SbF5

+

COClF

O2

ð4Þ

Carbonyl chloride fluoride is formed by thermal decomposition of chlorofluoro carbons like CCl2F2 with titanium dioxide catalyst (Equation (5)), as well as by dielectric discharge . They are also formed by the oxidation of chlorofluoro carbons with ozone (Equation (6)). CF2Cl2

+

TiO2

O2

CFCl3

+

COFCl

+

O3

Other products

ð5Þ

COFCl

ð6Þ

Carbonyl chloride fluoride is also formed in the oxidation of hydrofluorocarbons with either chlorine or other oxidants (Equation (7)). CHFCl2

6.14.3.1.2

+

Cl.

Air

COFCl

Air

Cl.

+

H3CCFCl2

ð7Þ

Carbonic bromide fluoride

Photooxidation of tribromofluoromethane in an oxygen atmosphere containing ozone showed the formation of carbonyl bromide fluoride (Equation (8)) . This compound like other different carbonyl dihalides has been spectroscopically studied, specifically its NMR and mass spectra .

414

Functions Containing a Carbonyl Group and at Least One Halogen CFBr3

6.14.3.1.3

O3

+

ð8Þ

COFBr

Carbonic fluoride iodide

The synthesis of carbonic fluoride iodide was reported in COFGT (1995) by a reaction of iodine pentafluoride with carbon monoxide under pressure, and no new synthetic methods for this compound have been reported, up to 2003.

6.14.3.2

One Chlorine and Bromine or Iodine

6.14.3.2.1

Carbonic bromide chloride

Carbonyl bromide chloride has been prepared by the insertion reaction of carbon monoxide with bromine chloride , a readily available brominating reagent (Equation (9)) . BrCl

+

CO

ð9Þ

COBrCl

Carbonyl bromide chloride has also been prepared by the photochemical oxidation of bromochlorohydrocarbons such as, dibromochloromethane and bromodichloromethane, with ozone (Equation (10)) . HCBr2Cl + O3

COBrCl + Others

O3 + H2CBrCl

ð10Þ

Like other carbonyl dihalides, carbonyl bromide chloride has been studied for its spectral behavior, like that of NMR and mass spectra .

6.14.3.2.2

Carbonic chloride iodide

As was the case in COFGT (1995) , carbonic chloride iodide has not yet (in late 2003) been reported.

6.14.3.3

One Bromine and Iodine

6.14.3.3.1

Carbonic bromide iodide

As in COFGT (1995) , no synthetic method for this compound, carbonic bromide iodide, has been reported, up to the end of 2003.

6.14.4

6.14.4.1

CARBONYL HALIDES WITH ONE HALOGEN AND ONE OTHER HETEROATOM One Halogen and One Oxygen

The general methods used for the syntheses of these haloformate esters, reported in COFGT (1995), are summarized in Scheme 4 . The three possible approaches are: first, the nucleophilic displacement of one of the halogen of a dihalo carbonyl with an alcohol to give the haloformates; second, the insertion of carbon monoxide on organo hypohalites; and third, the halogen exchange reaction of one haloformate ester to another haloformate ester by using a halide ion source.

Functions Containing a Carbonyl Group and at Least One Halogen COX2

ROH

ROCl

ROCOX

–HX

415

CO

X1–

ROCOX1 +

X–

Scheme 4

6.14.4.1.1

Fluoroformate esters

A method for the production of aliphatic fluoroformates, where carbonyl fluoride is esterified with aliphatic alcohols (e.g., t-butanol) in an ether at 20
C to +50
C, is described. The method is carried out using carbonyl fluoride obtained by reacting phosgene with surplus powdered sodium fluoride whose granules have a specific surface of 0.1 m2 g1 and/or an average diameter of 20 mm. This method enables the preparation of unstable fluoroformates (e.g., t-Bu fluoroformate) in excellent yields (Equation (11)) .

OH

+

COCl2

NaF

ð11Þ OCOF

One of the fluoroformates, 9-fluorenylmethyl fluoroformate, is a useful reagent for the largescale synthesis of dipeptide-free Fmoc (9-fluorenylmethoxycarbonyl) amino acids. 9-Fluorenylmethyl fluoroformate (Fmoc-F) is an inexpensive and effective reagent, which is available in large quantities for the synthesis of Fmoc-amino acids .

6.14.4.1.2

Chloroformate esters

Next to phosgene, chloroformate esters are the most important industrial compounds considered in this chapter. Significant research has been done on the transformation of these compounds into other compounds. Chloroformates are much easier to handle than phosgene and the difference in reactivity of the two leaving groups has been exploited in its chemistry. Diphosgene or trichloromethyl chloroformate, a versatile reagent in organic synthesis, is reviewed. Its reactions with amines, alcohols, and others have been discussed . Similarly, another chloroformate, methyl chloroformate, has been reviewed for its chemistry as well as its hazardous nature . As mentioned earlier, because of its importance as an industrial chemical, procedures for the storage and transport of chloroformate esters with reduced decomposition are well documented and regulated. For example, using polymer surface coatings of polyethylene for storage vessels as well as transport pipes decreases the decomposition of ethyl chloroformate . Chloroformates with the simplest alkyls, such as methyl, ethyl, or isobutyl, are used as general derivatizing agents in gas chromatography. The use of chloroformates in this regard in various disciplines has been reviewed . The preparation and application of chloroformates, for the immobilization of enzymes, have been described .

(i) From phenols and phosgene A continuous process is reported for the preparation of monofunctional aromatic chloroformates. Thus para-cumylphenol in methylene chloride reacted with phosgene in the presence of excess of aqueous sodium hydroxide gave a very good yield of the chloroformate with trace amounts of the diaryl carbonate impurity (Equation (12)). Other similar approaches are also known .

416

Functions Containing a Carbonyl Group and at Least One Halogen O OH Cl

O

NaOH

ð12Þ

COCl2

+

Synthesis and application of 3,5-di-t-butylbenzyl chloroformate for the protection of amino functions and the improvement of solubility in polyurethane synthesis have been reported (Equation (13)). O OH +

COCl2

NaOH

O

Cl

ð13Þ

Arylene bis(chloroformates), precursors for cyclic oligomeric carbonate monomers, are prepared by three methods: using PhNEt2 to scavenge HCl, by low pH, low-temperature interfacial condensation of bisphenols with phosgene, and using Ca(OH)2 in interfacial condensation with phosgene (Equation (14)). O OH

Cl

O +

2COCl2

OH

AIBN

ð14Þ O

Cl O

Chiral resolution of 1,10 -binaphthalene-2,20 -diol and its ()-menthyl chloroformate derivatives by high-performance liquid chromatography has been reported using the urea derivative as a chiral stationary phase .

(ii) From alcohols and phosgene Chloroformates are prepared by dissolution of water-soluble alcohols having a melting point 20
C in H2O and reaction with phosgene. Trimethylolpropane reacted with phosgene in H2O under ice cooling for 1 h to give 72% trimethylolpropane trischloroformate (Equation (15)). CH2OH CH2OH CH2OH

CH2OCOCl +

3COCl2

CH2OCOCl CH2OCOCl

ð15Þ

Chloroformates are prepared by treating alcohols with molecular sieves followed by reaction with phosgene. Thus, s-butyl alcohol was treated with molecular sieves at room temprature for 15 h, and reacted with phosgene to give 96% s-butyl chloroformate (Equation (16)). + OH

ð16Þ

COCl2 OCOCl

Chloroformates have also been prepared by phosgenation of alcohols under pressure , under reduced pressure , as well as in the presence of activated carbon . Under the reduced pressure conditions, phosgene has been replaced by either diphosgene or triphosgene .

Functions Containing a Carbonyl Group and at Least One Halogen

417

Hydroxyalkyl (meth)acrylate chloroformates are prepared by reaction of hydroxyalkylated acrylate or methacrylate esters with chloroformylation agents in the presence of H2O. 2-Hydroxyethyl methacrylate was treated with COCl2 in the presence of H2O at 0
C for 2 h to give 78% chloroformate (Equation (17)). CH3 +

O

COCl2

OH

O

CH3

NaOH

O O

ð17Þ OCOCl

Purification of methacryloyl-terminated chloroformates is done in high yields by mixing them with hydrocarbon solvents and removing polymerized product by filtration . A convenient process for the synthesis of glyoxylate-derived chloroformates has been developed. The approach involves the reaction of glyoxylate esters with triphosgene and pyridine in various solvent systems. These novel glyoxylate-derived chloroformates are multifunctional, possessing a chloroformate, ester, and haloalkyl moiety . The synthesis of benzyl chloroformate from benzyl alcohol and phosgene was studied. The application of benzyl chloroformate in polypeptide synthesis has been introduced .

(iii) Chlorination of carbonate Trichloromethyl chloroformate is prepared from methyl formate or methyl chlorocarbonate in reactor under stirring using an ultraviolet (UV) high-pressure mercury lamp (Equation (18)). +

CH3OCOOCH3

Cl2

Cl3COCOCl

ð18Þ

(iv) Preparation of
-halogenated chloroformates from aldehyde and phosgene
-Chlorinated chloroformates, useful as pharmaceutical intermediates, are prepared by the reaction of phosgene with an aldehyde in the presence of a catalyst comprising alkyl-substituted guanidines, hexa-substituted guanidinium chlorides, or bromides. Thus, acetaldehyde reacted with phosgene in the presence of pentabutylguanidine, producing 1-chloroethyl chloroformate in 88.9% yield (Equation (19)). Similarly, benzaldehyde-derived chloroformates have also been made and used in the synthesis of novel insecticides . H + O

COCl2

O

Cl

ð19Þ O

Cl

(v) Preparation of
-halogenated chloroformates by halogenation of chloroformates An improved process for concurrently preparing 1-chloroethyl chloroformate and 2-chloroethyl chloroformate with improved selectivity, was achieved by chlorination of ethyl chloroformate, optionally in presence of a free radical initiator. Ethyl chloroformate was chlorinated with chlorine gas in the presence of a free radical initiator 2,2-azobis(2-methylpropanenitrile) to give a mixture of 1-chloroethyl- and 2-chloroethyl-chloroformate . Preparation of trichloromethyl chloroformate has been achieved by a photochemical chlorination process of methyl chloroformates. For example, this process comprises adding PCl5 to methyl chloroformate and heating to 30–50
C under light, treating with chlorine for 70–80 h while absorbing HCl with lime water (Equation (20)). CH3OCOCl

+

PCl5

Cl3COCOCl

ð20Þ

Preparation of chloromethyl chloroformate was done by free radical chlorination, using sulfuryl chloride and 2,20 -azobisiobutyronitrile (AIBN), of methyl chloroformate. The product, chloromethyl chloroformate, thus obtained was reacted with alcohols to give alkoxycarbonyloxymethyl

418

Functions Containing a Carbonyl Group and at Least One Halogen

chlorides as intermediates for pharmaceuticals (Equation (21)). Chloromethyl chloroformate has also been used in the synthesis of trichloroacryloyl chloride . CH3OCOCl

+

SO2Cl2

ð21Þ

ClCH2OCOCl

(vi) Nonphosgene methods Chloroformate esters are prepared by treating 1 mol of HCl or nitrosyl chloride with 0.1–100 mol of nitrite esters and CO in the presence of Pt-group metal catalysts. A mixture of HCl, CO, MeONO, NO, and MeOH (0.6:6:7:2:8) was passed through PdCl2/alumina at 60
C to give 100% ClCO2Me (Equation (22)).

HCl

+ CO

+

MeONO +

NO +

MeOH

PdCl2/Al2O3

MeOCOCl

ð22Þ

Chloroformate esters are also prepared by treating 1 mol of chlorine with 0.1–100 mol of nitrite esters and CO in the presence of supported Pt-group metal catalysts. A mixture of chlorine, CO, MeONO, NO, and MeOH (1:7:6:2:6) was passed through PdCl2/alumina at 120
C to give 18% ClCO2Me (based on chlorine) . Similar preparations are reported for the synthesis of alkyl chloroformate where the methyl nitrite has been replaced with alkyl nitrite ester . Methyl chloroformate has been synthesized via direct interaction of palladium bis(methoxycarbonyl) complexes with CuCl2 (Equation (23)). ClCOOMe has been obtained in 80% yield by reaction of [PdL2(COOMe)2] [L2 = 2,20 -bipyridine (bipy) or 1,10-phenanthroline (phen)] with CuCl2. [Pd (bipy) (COOMe)2]

+

4CuCl2

THF

ð23Þ

MeOCOCl

Benzyl chloroformate synthesis using carbon monoxide as a carbonyl source has been reported . A novel nonphosgene synthetic method for benzyl chloroformate has been established. SMe O–benzyl carbonothioates were prepared by the carbonylation of benzyl alcohols with carbon monoxide and sulfur (or carbonyl sulfide) in the presence of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) followed by esterification using methyl iodide in good yields. Then, the benzyl chloroformates were successfully synthesized by the chlorination of SMe O–benzyl carbonothioates using sulfuryl chloride in excellent yields (Equation (24)). CH2OH +

CO

S/DBU

CH2OCOSMe

SCl2

CH2OCOCl

ð24Þ

A novel synthetic method for benzyl chloroformate using carbon monoxide or carbonyl sulfide as a carbonyl source has been established. Benzyl chloroformate was successfully synthesized by the chlorination using sulfuryl chloride of PhCH2O2CSMe, which was prepared by the carbonylation of benzyl alcohol with carbon monoxide and sulfur (or carbonyl sulfide) in the presence of DBU (1,5-diazabicyclo[5.4.0]undec-5-ene) followed by esterification using methyl iodide .

(vii) Other chloroformates An oxime of an estradiene derivative was reacted with phosgene or diphosgene to give a chloroformate derivative (Equation (25)).

419

Functions Containing a Carbonyl Group and at Least One Halogen HO

O

Cl

N

N

O OR

H Me

OR

H CH2OR

Me

COCl2

CH2OR

ð25Þ

H

H O

O

Methyl 11C-labeled methyl chloroformate, a novel 11C-acylating agent, was formed by the reaction of 11C-labeled methanol and phosgene .

6.14.4.1.3

Bromoformate esters

From COFGT (1995) it is known that these compounds, bromoformate ester, are prepared by two approaches. One using the reaction of alcohols with carbonyl dibromide, and two using the bromide exchange reaction on the chloroformates. Up until the end of 2003, no new approaches have been reported for making bromoformate esters.

6.14.4.1.4

Iodoformate esters

Stable iodoformates were reported in COFGT (1995) . The first iodoformate, 9-triptycyl iodoformate, was made photochemically from its 9-triptycyl monoester of oxalic acid. Iodoformates have also been synthesized by using the iodide exchange reaction on chloroformates. Up until the end of 2003, there have not been any new approaches to the synthesis of iodoformates.

6.14.4.2

One Halogen and One Sulfur

Similar to the oxygen system of haloformate esters, here again in the halothiolformate esters the synthetic methods mentioned in COFGT (1995) are summarized in Scheme 5. The insertion of carbon monoxide to sulfenyl halide, the nucleophilic displacement of one of the halogen in carbonyl dihalide with a thiol, and the halogen exchange on a halothiolformate are the three general routes to halothiolformate esters. COX2

RSH –HX

RSCOX

RSCl

CO

X1–

RSCOX1 + X–

Scheme 5

Structures and conformations of (fluorocarbonyl)trifluoromethylsulfane and that of (chlorocarbonyl)trifluoromethylsulfane have been determined by gas electron diffraction, vibrational spectroscopy, and theoretical calculations .

6.14.4.2.1

Fluorothiolformate esters

The preparation of fluorocarbonyl sulfenyl bromide from fluorocarbonyl sulfenyl chloride and trimethylsilyl bromide was described in COFGT (1995) . A photochemical

420

Functions Containing a Carbonyl Group and at Least One Halogen

study has been done with this compound. Under photochemical conditions, this fluorothiolformate ester eliminates carbon monoxide to give sulfur bromide fluoride .

6.14.4.2.2

Chlorothiolformate esters

Here one should be careful not to confuse the thiono formates, with sulfur in the thiocarbonyl group (C¼S), with that of thiol formates, with sulfur in the thiol group (CS). In some cases the thiono formates could rearrange to thiol formates as seen with the allylic thiono chloroformates.

(i) From phosgene and thiols Thiochloroformates are manufactured with reduced amount of by-products by reacting thiols with phosgene in the presence of ureas as a catalyst. For example, phosgene and n-octanethiol with N,N-dimethylpropyleneurea as the catalyst, gave mainly n-octylthio chloroformate with very small amounts of thiocarbonate and disulfide as impurities .

(ii) By rearrangement of allylic thionochloroformates Treatment of allylic alcohols with thiophosgene and pyridine gives thiolo chloroformates directly at rt, presumably via a very rapid [3,3]-sigmatropic rearrangements of thionochloroformates. Synthesis of allyl thionochloroformate from allyl alcohols sodium hydride and thiophosgene at low temperature and warming up to rt supports this finding . Thiophosgene, as seen above, has been used in the synthesis of thiochloroformates. General reviews on the industrial synthesis of thiophosgene and derivatives are available .

6.14.4.2.3

Bromothiolformate esters

These compounds, bromothiolformate esters, have rarely been reported . Bromide exchange on a fluorothiolformate has been reported to make trifluoromethyl bromothiolformate and carbon monoxide insertion on methylsulfenyl bromide has been used to make methyl bromothiolformate. Up until the end of 2003, new methods for the synthesis of bromothiolformate esters were not found in the literature.

6.14.4.2.4

Iodothiolformate esters

Similarly to what was reported in COFGT (1995) , the present authors did not find any reference to this class of compounds in the period up to 2003.

6.14.4.3

One Halogen and One Nitrogen

The general methods reported in COFGT (1995) for the preparation of the above-mentioned compounds are summarized in Scheme 6. The reaction of carbonyl dihalide with primary, secondary, and tertiary amines leads to carbamoyl halides, which in the case of a primary amine could further be converted into isocyanates, an important industrial compound. The secondary amine carbamoyl halides could also be synthesized from either carbon monoxide insertion into dialkyl haloamines, or halogenation of N,N-dialkyl formamides. Halo cyanato and halo thiocyanato carbonyl compounds are made by nucleophilic displacement of the corresponding anions source with a carbonyl dihalide.

421

Functions Containing a Carbonyl Group and at Least One Halogen SCNCOCl SCN– R1R2R3N

R1R2R3N+COCl Cl

RNH2

COCl2

HCl

RNHCOCl

RNCO

–

NCO–

R1R2NH R1R2NCl

OCNCOCl

R1R2NCOCl

CO

Cl2 R1R2NCOH

Scheme 6

6.14.4.3.1

Carbamoyl fluorides

Carbamoyl fluorides formed by the addition of hydrogen fluoride on to an isocyanate are used as fluorinating agents, specifically for converting a chloride into a fluoride. For example, para(trifluoromethyl)phenyl isocyanate is prepared from para-(trichloromethyl)phenyl isocyanate and hydrogen fluoride in the presence of tin tetrachloride. A carbamoyl fluoride is suggested as the intermediate in this reaction, which is isolated in small amounts from the reaction mixture (Scheme 7).

O C

O C

O HN

N +

HF

F

HN

N

SnCl4

CCl3

O F

+

CCl3

CF3 97%

CF3 3%

Scheme 7

Experimental and theoretical investigations of the geometry and conformation of fluorocarbonyl isocyanate and fluorocarbonyl azide were carried out. These were compared with that of their corresponding precursors, formyl isocyanate and formyl azide, respectively. The present authors warn that fluorocarbonyl azide is an explosive and should be handled only with proper safety precautions and in millimolar quantities . N-fluoroformyliminotrifluoromethylsulfur fluoride, FCON¼S(F)CF3, has been studied using vibration spectroscopy and theoretical calculations .

6.14.4.3.2

Carbamoyl chlorides

Carbamoyl chlorides have also been made using the phosgene substitute, trichloromethyl carbonate or triphosgene. The effects of solvent, reaction time and temperature, feed ratio, and dosage of nucleophile on the yield have been discussed . Solid-phase synthesis of ureas of secondary amines via carbamoyl chloride has been reported. Secondary amines attached to a solid support such as the Wang resin can be converted to the corresponding carbamoyl chlorides by treatment with phosgene or triphosgene .

422

Functions Containing a Carbonyl Group and at Least One Halogen

A novel synthesis of 3-substituted 1-chlorocarbonylimidazolidin-2-ones using triphosgene or bis(trichloromethyl)carbonate has been reported. The yields and purity of the products obtained are better than those obtained by a conventional method using phosgene . New and efficient palladium-catalyzed routes to carbamoyl chlorides have been reported. The palladium-based catalytic system is very active and operates in two steps, avoiding the synthesis of phosgene, but making use of carbon monoxide and chlorine as in phosgene chemistry. Primary amines lead directly to isocyanates and the secondary amines lead to carbamoyl chlorides .

6.14.4.3.3

Carbamoyl bromides

Carbamoyl bromides or N-bromocarbonyl compounds have been made as reported in COFGT (1995) using the general methods used for the preparations of carbamoyl halides. The addition of hydrogen bromide to an isocyanate or the exchange of chloride in carbamoyl chlorides with a bromide source are the two common approaches to the synthesis of carbamoyl bromides. Up until the end of 2003, new methods for the synthesis of carbamoyl bromides have not been seen in the literature.

6.14.4.3.4

Carbamoyl iodides

These compounds are suggested to be not very stable according to COFGT (1995) . Only one approach, that of addition of hydrogen iodide to an isocyanate, has been reported for the synthesis of carbamoyl iodides. There have been no new reports on the synthesis of this class of compounds, up to the end of 2003.

6.14.4.4

One Halogen and One Phosphorus

Synthesis of compounds belonging to this section, mentioned in COFGT (1995) , is summarized in Scheme 8. The trivalent phosphorus compounds could further react either by elimination of CO to give phosphorus halide, or by elimination of hydrogen halide to give phosphaketene. The reaction of trisalkoxy phosphorus with carbonyl dihalide gives alkyl halide and (dialkoxyphosphinyl)formyl halide, a pentavalent phosphorus compound (Arbuzov reaction).

R1R2PSiMe3

COCl2

R1R2PCOCl

R1R2PCl

R2 = H

R1P=C=O (RO)2POCOCl + RCl

(RO)3P + COCl2

Scheme 8

6.14.4.4.1

Chlorocarbonyl derivatives of phosphorus(III)

The reaction of triphenylmethyl-substituted primary and secondary phosphines with phosgene has been studied. The nature of the product with the trityl-substituted primary phosphine depends on the nature of the solvent. In toluene, the initially formed chlorocarbonyl phosphorus compound is stable, but it loses CO in methylene chloride to give a chlorophosphine, and loses HCl in ether

Functions Containing a Carbonyl Group and at Least One Halogen

423

solvent to give a phosphaketene, which dimerizes. In the case of the trityl-substituted secondary phosphine, the nature of the product depends on the nature of the second substituent on phosphorus. When the substituent was phenyl, the initial adduct, chlorocarbonyl phosphorus compound, was very stable, and when the substituent was a t-butyl the initial adduct readily lost the CO to give the corresponding chlorophosphine compound . In the same paper the reaction of diphosphine with phosgene was reported. It was found to be inert in the absence of hydrogen chloride. In the presence of HCl the PP bond was cleaved to give the primary phosphine and the chlorophosphine as the products . All these reactions are summarized in Scheme 9. COCl2/ether

COCl2/CH2Cl2

Ph3CPHCOCl

Ph3CPH2

Ph3CPHCOCl –CO

COCl2/ toluene

Ph3PHCl

–HCl

(Ph3CPCO)2

Ph3CPHCOCl

Ph3CPCl2 + Ph3CPRCl

(Ph3CPH)2

COCl2 R

= But

COCl2

Ph3CPRH

COCl2 HCl

Ph3CPRCOCl

R = Ph

Ph3CPH2 + Ph3CPHCl

Scheme 9

Another way these chlorocarbonyl phosphorus compounds have been made is via anhydrous HCl hydrolysis of phospha–urea compound, where the cleavage of a PCO bond occurs leading to a phosphine and a chlorocarbonyl phosphorus compound. This reaction is depicted in Scheme 10 .

HCl (Ph3CPH)2CO

Ph3CPH2

+

Ph3CPHCOCl

Scheme 10

6.14.4.4.2

Chlorocarbonyl derivatives of phosphorus(V)

A facile one-pot preparation of phosphonothiolformates, useful reagents for the synthesis of carbamoylphosphonates, was accomplished by sequential reaction of phosgene solution with alkane thiols, to form the chlorothiolformates, followed by Arbuzov reaction with trialkylphosphites .

6.14.4.5

One Halogen and One Arsenic, Antimony, or Bismuth

As in COFGT (1995) any reports on these compounds were not seen.

6.14.4.6

One Halogen and One Metalloid (Boron, Silicon, or Germanium)

Preparation of this class of compounds has not been reported, in the period up to 2003, as was similarly observed in COFGT (1995) .

424 6.14.4.7

Functions Containing a Carbonyl Group and at Least One Halogen One Halogen and One Metal

The organometal carbonyls reactions with halogens are known to give organometal carbonyl halides . These compounds could further lose carbon monoxide to give organometal halides. The synthesis of metal bromides and their bromide oxides by the use of carbonyl dibromide must have gone through bromocarbonyl metal intermediates. Carbonyl dibromide reacted with a wide selection of d- and f-block transition-metal oxides to form either the metal bromide or bromide oxide. The reaction was done, by heating the metal oxides at 125
C for 10 days with excess carbonyl dibromide in a sealed tube. Under these conditions V2O5, MoO2, Re2O7, Sm2O3, and UO3 were converted into VOBr2, MoO2Br2, ReOBr4, SmBr3, and UOBr3, respectively . No new synthetic method for this class of compounds has been seen in the period 1993–2003. All the references were to complexes with halogens and carbonyls attached directly to the metals, which are beyond the scope of this chapter.

6.14.4.7.1

Halocarbonyl complexes of first transition metal series (iron and chromium)

No new synthetic methods for this class of compounds have been reported in the period 1993–2003, other than those mentioned in COFGT (1995) .

6.14.4.7.2

Halocarbonyl complexes of second transition metal series (ruthenium and rhodium)

No new synthetic methods for this class of compounds have been reported in the period 1993–2002, other than those reported in COFGT (1995) .

6.14.4.7.3

Halocarbonyl complexes of third transition metal series (rhenium and iridium)

No new synthetic method for this class of compounds have been reported, other than those mentioned in COFGT (1995) , briefly discussed above.

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425

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Functions Containing a Carbonyl Group and at Least One Halogen

427

Biographical sketch

Ramiah Murugan was born in Madurai, India. He obtained B.Sc. in chemistry in 1975 from American College, Madurai, Tamil Nadu, India and an M.Sc. in chemistry in 1977 from Madurai University. After four years of Junior Scientist work at Madurai University, he joined Professor A. R. Katritzky’s group at the University of Florida, USA and obtained his Ph.D. in 1987. He stayed there for two more years doing postdoctoral work in the area of high-temperature aqueous organic chemistry. He joined Reilly Industries in 1989 and is currently a Senior Research Associate. His research interests include synthesis of intermediates for pharmaceuticals, agrochemical products, and performance products; mechanistic studies; catalysis; polymer chemistry; and process development.

Subbarao Yarlagadda received his M.Sc. in organic chemistry from Andhra University, Waltair, India. He obtained his Ph.D. in 1991 from the Indian Institute of Chemical Technology (IICT), Hyderabad, India. His doctoral work was chiefly on selective organic transformations by using a new class of heterogenized homogeneous catalysts. Later, he joined as a postdoctoral fellow with Professor M. Graziani at the University of Trieste, Italy under the UNIDO program, and worked on polydentate ligands and their metal complexes for an oxidative amination reaction. From 1992 to 1996, he was a staff scientist in Dr. A.V. Ramarao’s group at IICT, India, and worked on the synthesis of fine and specialty chemicals, pharmaceutical intermediates by using zeolite catalysts. In 1996, he joined Professor P. A. Jacobs at the Katholieke University of Leuven, Belgium and worked on Mesoporous zeolites and homogeneous catalysts for the synthesis of specialty chemicals. Since July 1998, he has been with Reilly Industries, Indianapolis, IN, USA as a Research Associate. His current interests include the process development, invention of new routes for the existing products, synthesis of fine and specialty chemicals, development of new catalysts for the synthesis of pharmaceutical and agrochemical intermediates, and vitamins.

# 2005, Elsevier Ltd. All Rights Reserved No part of this publication may be reproduced, stored in any retrieval system or transmitted in any form or by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers

Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 409–427

6.15 Functions Containing a Carbonyl Group and at Least One Chalcogen (but No Halogen) H. ECKERT Technical University Munich, Garching, Germany 6.15.1 CARBONYL CHALCOGENIDES WITH TWO SIMILAR CHALCOGEN FUNCTIONS 6.15.1.1 Two Oxygen Functions 6.15.1.1.1 Carbonates from phosgene and substitutes, chloroformates 6.15.1.1.2 Carbonates from carbon oxides and carbonate salts 6.15.1.1.3 Carbonates from ureas 6.15.1.1.4 Cyclic carbonates and transesterification 6.15.1.1.5 Acylcarbonates 6.15.1.1.6 Carbonates by iodolactonization 6.15.1.1.7 Polycarbonates 6.15.1.2 Two Sulfur Functions 6.15.1.2.1 Dithiocarbonates by [3,3]-sigmatropic rearrangement 6.15.1.2.2 1,3-Dithiol-2-ones by xanthogen disulfide-alkyne cycloaddition 6.15.1.2.3 Mixed methods 6.15.1.3 Two Selenium Functions 6.15.2 CARBONYL CHALCOGENIDES WITH TWO DISSIMILAR CHALCOGENIDE ATOM FUNCTIONS 6.15.2.1 Oxygen and Sulfur Functions 6.15.2.1.1 Thiocarbonates from activated carbonates 6.15.2.1.2 Thiocarbonates from alkoxycarbonylsulfenyl chlorides 6.15.2.1.3 Thiocarbonates from carbonothioic acid salts 6.15.2.1.4 Other methods 6.15.2.2 Other Dissimilar Chalcogenide Functions 6.15.2.2.1 Oxygen and selenium functions 6.15.2.2.2 Oxygen and tellurium functions 6.15.2.2.3 Sulfur and selenium functions 6.15.3 CARBONYL CHALCOGENIDES WITH A CHALCOGEN FUNCTION AND ONE OTHER HETEROATOM FUNCTION 6.15.3.1 Oxygen and Nitrogen Functions 6.15.3.1.1 Carbamates from chloroformates or phosgene equivalents 6.15.3.1.2 Carbamates from isocyanates 6.15.3.1.3 Carbamates from N,N0 -carbonyldiimidazole (CDI) 6.15.3.1.4 Carbamates from carbonates or dicarbonates 6.15.3.1.5 Carbamates from carbon oxides 6.15.3.1.6 Carbazates 6.15.3.1.7 Azidoformates 6.15.3.2 Oxygen and Phosphorus Functions 6.15.3.2.1 Phosphinecarboxylates by the Arbuzov reaction and related methods 6.15.3.3 Oxygen and Other Heteroatom Functions 6.15.3.3.1 Oxygen and boron functions

429

430 430 430 432 433 433 434 434 435 435 435 435 436 436 436 436 436 437 437 438 438 438 439 440 440 440 440 441 441 442 443 444 444 444 444 445 445

430

Functions Containing a Carbonyl Group and at Least One Chalcogen

6.15.3.4 Sulfur and Nitrogen Functions 6.15.3.4.1 Thiocarbamates from chlorothioformates and amines 6.15.3.4.2 Thiocarbamates from carbamoyl chlorides and thiols 6.15.3.4.3 Thiocarbamates from isothiocyanates and alcohols 6.15.3.4.4 Thiocarbamates from alkylamide salts, carbon monoxide, and sulfur 6.15.3.4.5 Thiocarbamates from [3,3]-sigmatropic rearrangement 6.15.3.4.6 Thiocarbamates from trichloroacetyl chloride, thiols, and amines 6.15.3.5 Sulfur and Phosphorus Functions 6.15.3.5.1 Phosphonothioformates 6.15.3.6 Other Mixed Systems 6.15.3.6.1 Selenium and nitrogen functions 6.15.3.6.2 Tellurium and nitrogen functions

6.15.1

445 445 445 446 446 446 447 447 447 447 447 449

CARBONYL CHALCOGENIDES WITH TWO SIMILAR CHALCOGEN FUNCTIONS

An overview on all functional group transformations, which can be accomplished by use of phosgene as well as by use of about 70 phosgene substitutes and equivalents, has been presented in 2003 by Cotarca and Eckert in Phosgenations—A Handbook .

6.15.1.1

Two Oxygen Functions

Carbonic acid is principally a difunctional carboxylic acid; therefore, manifold preparative accesses for a great variety of its organic derivatives exist, which differ widely in rate and selectivity of reactions and reagents. Some reviews have been published .

6.15.1.1.1

Carbonates from phosgene and substitutes, chloroformates

Phosgene, as the formal carboxylic acid dichloride of carbonic acid, is a highly reactive reagent, which affords high turnovers and good yields. Thus, both symmetrical and unsymmetrical dicarbonates, the latter via chloroformates, can easily be produced. A key intermediate of the decalin part of azadirachtin, an antifeedant, insect growth regulatory, and reproductive effective substance from the Neem tree Azadirachta indica, has been prepared by carbonylation of the alcohol with methyl chloroformate, affording the carbonate (Equation (1)) . O

TBDMS O

O

O

TBDMS O

O

Cl-CO2Me

OH O

O

ð1Þ

Pyridine, DCM 0 °C, 70 min, then, rt, 40 min 70%

O O

OMe

O O

During a nice enantioselective total synthesis of epothilone A using multifunctional asymmetric catalysis (Suzuki cross-coupling of fragment A with fragment C, followed by Yamaguchi lactonization), the reaction of the aldehyde with TMS-acetylide affords an alcohol, which is methoxycarbonylated with methyl chloroformate resulting the carbonate (Equation (2)) . _

Li + THF, –78 °C 40 min

i. TMSS N CHO OTBS

O

S N

O

ð2Þ

O

ii. MeOCOCl 30 min, 79%

OTBS

TMS

431

Functions Containing a Carbonyl Group and at Least One Chalcogen

A carbonate intermediate for the synthesis of functionalized ‘‘pyridoindoles,’’ which have attracted great interest by virtue of their cytotoxic activity toward leukemia cells, has been prepared by using ethyl chloroformate . Phenyl chloroformate has been employed in the cyclocarbonylation reaction to prepare an intermediate in synthesis of solanoeclepin A . Functionalization of taxol, which is a powerful anticancer drug, in the position 2, is an important pharmaceutical tool. This can be achieved advantageously by cyclocarbonylation of the 1,2-diol at 13-deoxy-7-TES baccatin III with phosgene yielding 95% of the corresponding 1,2-cyclocarbonate (Equation (3)), which will further be reacted with alkyllithium compounds to afford 2-acylbaccatin derivatives under ring opening of the 1,2-cyclocarbonate . AcO

O

AcO

OTES

O

OTES

COCl2 1

2

H

HO

OH

Pyridine 25 °C, 30 min 95%

O OAc

1

2

H

O

O

ð3Þ

O OAc

O

A highly interesting synthetic route for preparing intermediates of ‘‘retinal’’ comprises a palladium-catalyzed transformation of an ‘‘yne-carbonate’’ into an ‘‘allenyl enal.’’ The carbonate is prepared by unsymmetrical carbonylation of propargylic alcohol and silyl enol ether with phosgene, each step with 90% yield (Scheme 1) . Ph

Ph

Cat. Pd(PPh3)4

i. BuLi O

OH ii. COCl2

Ph

O

CHO

–CO2

O

90%

iii. TMSO MeLi 90%

Scheme 1

In all reactions previously described phosgene is the basic chemical for the preparation of carbonates in a direct way as well in the synthesis of the chloroformates. Phosgene itself is a poisonous gas which was discovered in 1812 by Davy from the action of sunlight on carbon monoxide and chlorine. Extensive safety precautions are required to prevent exposure to phosgene during handling. In order to avoid the difficulties associated with the toxicity of phosgene gas, equivalents and substitutes for phosgene as well as the ‘‘safety phosgenation’’ have been developed . Another often used phosgene equivalent to accomplish carbonylation reactions is the solid 1,10 -carbonyldiimidazole (CDI). The conversion of (RS)-sec-phenethyl alcohol to its 2,2,2-trifluoroethylcarbonate, which is needed for the resolution of ‘‘chiral alcohols,’’ by using CDI in good yield has been described (Scheme 2) . O

O O

OH

N N

O

N

CDI

N

N

O

N CF3

OH

10% DMAP DCM, rt, 24 h 85%

DCM, rt, 2 h 98%

Scheme 2

O

CF3

432 6.15.1.1.2

Functions Containing a Carbonyl Group and at Least One Chalcogen Carbonates from carbon oxides and carbonate salts

The bulk chemical diphenyl carbonate (DPhC), which is an important reagent in the manufacture of polycarbonates, has been produced by the oxidative carbonylation of phenol with carbon monoxide (CO) and air-oxygen catalyzed by Pd dinuclear complexes and redox catalyst (Equation (4)) . Reaction proceeds smoothly on a Pd dinuclear complex bridged with a pyridylphosphine ligand [Pd2(Ph2Ppy)2X2] and redox catalyst along with ammonium halide in the presence of CO and air at 100
C and the TOF reaches 19.21 (mol-DPhC/mol-Pd h). OH CO, O2

O H2O

+

2 Pd2(Ph3PPy)2Cl2 Redox catalyst

ð4Þ

O

O

DPhC

NH4Cl, 100 °C

Dialkylcarbonates have been prepared from CO2 and alkanols under Appel conditions by using tri-(1-butyl)-phosphane, tetrabromomethane, and cyclohexyl tetramethylguanidine (CyTMG). This strong, hindered, and non-nucleophilic base is more effective than other bases such as DBU. DMF is the solvent of choice (Equation (5)) . Yields of dialkyl carbonates derived from various primary alkanols are 54–91%; from secondary alkanols they are 14–22%. + 2ROH

+

n-Bu3P

CyTMG

CBr4

DMF 54–91%

CO2 +

+

O OR

n-Bu3P=O

ð5Þ

OR +

CHBr 3

A three-component coupling system of aliphatic alcohol/CO2/alkyl halide under a pressure of 160 psig CO2 and in the presence of a peralkylated guanidine has been applied to prepare dialkylcarbonates . Thus, di-1-butylcarbonate is obtained in 73% yield (by GC). An approach to synthesize ‘‘mixed’’ dialkylcarbonates employs the above three-component coupling system aliphatic alcohols/CO2/alkyl halides in the presence of Cs2CO3 and without pressure of CO2 (Scheme 3). This method shows a great variety in use of alcohols and alkyl halides (Table 1), reaction times are 2.5–23 h, yields of the resulting mixed dialkylcarbonates are 91–98% .

Ph

OH

Ph

OBu

O O

Cs2CO3 TBAI

DMF 23 °C, 3.5 h

_

Ph

O

Cs +

1-BuBr CO2

92% _

Ph

O

O

Cs +

O

Scheme 3

One of the most attractive synthetic goals starting from CO2 is the bulk chemical dimethylcarbonate (DMC). An approach is the organostannane-catalyzed reaction of dehydrated derivatives of methanol (ortho-ester and acetals) with ‘‘supercritical’’ CO2 . The reaction of acetals is especially attractive because the starting material is much less expensive compared with ortho-esters, and the co-produced acetone can be recycled (Scheme 4).

Functions Containing a Carbonyl Group and at Least One Chalcogen

433

Dialkyl carbonate formation using alcohols, halides, and CO2 in the presence of Cs2CO3

Table 1

Alcohol (ROH)

Halide (R0 -X)

4-Phenylbutanol

t-Butyl 2-bromoacetate Benzyl chloride Allyl bromide s-Butyl bromide n-Butyl bromide t-Butyl 2-bromoacetate Benzyl chloride n-Butyl bromide MPMCl

2-Phenylpropanol

Time (h)

Yield (%)

5 2.5 4 23 4.5 5 3 5 3

95 94 91 98 92 96 98 96 92

Source: .

O

O

Supercritical CO2 MeO cat. Me2Sn(OMe)2

O

O + OMe

+2 MeOH –H2O

Scheme 4

6.15.1.1.3

Carbonates from ureas

Processes to produce DMC in high yield are of great interest. There is a need for low-cost DMC, because it becomes more and more important in fuel application as a gasoline additive. DMC has many desirable properties: almost 3 times the oxygen content of methyl t-butyl ether (MTBE), good octane for blending (RON of 130), lower volatility than MTBE, and biodegradability. Reaction of methanol with urea to give DMC is a well-known low-yield synthesis, but the use of triethylene glycol dimethyl ether (triglyme) as a solvent, in conjunction with tin catalysts, affords high yields of DMC to be realized (Scheme 5) . More details on this process are also described in . O

O H2N

NH2 + 2MeOH

NH2

H2N

2NH3 + CO2 Diglyme tin-cat. 180 °C

+ H2O

O OMe + 2NH3

MeO

O 2MeOH +

CO2

98% MeO

OMe

+ H2O

DMC

Scheme 5

6.15.1.1.4

Cyclic carbonates and transesterification

Transesterification is used industrially to produce DMC and diethylcarbonate as shown in recent patents. Dowex MSA 1, CoYO, and Y2O3 are used as catalysts (Equation (6)) .

434

Functions Containing a Carbonyl Group and at Least One Chalcogen O

O

Cat. O

O

+ 2MeOH

OMe

MeO

+

OH

HO

ð6Þ

DMC

The above-presented process with CoYO as catalyst is also employed in the production of diphenyl carbonate (DPhC) in 95% yield from ethylene carbonate (EC) (Equation (7)) . It is a continuous process using a fixed bed reactor at 130
C, a pressure of 9 kg cm2, and an LHSV of 3 h1. O O

i. MeOH ii. PhOH O

O

Cat., 130 °C 95%

O

+

OH

HO

ð7Þ

O

DPhC

(i) Enzyme catalysis In a transesterification process by selective alkoxycarbonylation using enzymes in organic solvents as catalysts, the A-Ring precursor of vitamin D3 has been prepared. Candida antarctica lipase (CAL) is found to be the best catalyst in toluene (Equation (8)). Other enzymes are PSL and CVL, other solvents are THF and 1,4-dioxane, yields of alkoxycarbonylation products depend strongly on conditions and are 17–100%. Regioselective alkoxycarbonylation occurs only at the C-5-(R) hydroxy group .

Enzyme Cal Toluene

O + HO

O

O

N

30 °C, 4 h 100%

OH

ð8Þ

O O

O

OH

Enzymatic acylation in organic solvents has also been employed to synthesize water-soluble Paclitaxel derivatives. Thus, potential new ‘‘prodrugs’’ can be generated possessing high solubility in water. The approach involves an enzymatic acylation of ‘‘paclitaxel’’ with a bifunctional acylating reagent, catalyzed by enzyme ‘‘thermolysin’’ (from ‘‘bacillus thermoproteolyticus rokko’’) to give an activated carbonate dervative (conversion 83%) .

6.15.1.1.5

Acylcarbonates

A detailed review on di-t-butyldicarbonate (BOC2O), a widely used standard reagent for the introduction of the BOC-group, in its reactions with alcohols in the presence of DMAP is given by Hassner and Basel . Many general procedures for reactions of BOC2O with common alcohols affording O-BOC-derivatives and/or symmetrical carbonates are described (Equation (9)). O

O ROH +

But O

O

O But

BOC2O

6.15.1.1.6

MeCN

O

O

DMAP RO

OBut

+ RO

OR

ð9Þ

Carbonates

Carbonates by iodolactonization

An intermediate carbonate 1 for an iodolactonization reaction has been accomplished by using the acylcarbonate BOC2O in excellent yield of 98% .

Functions Containing a Carbonyl Group and at Least One Chalcogen

435

O-But H

O

O C6H11 1

6.15.1.1.7

Polycarbonates

For polycarbonates there is a huge and fast-growing market. They are excellent engineering thermoplastics and substitutes for metals and glass because of their good impact strength, heat resistance, and transparency, which makes it an ideal material for optical data-storage devices. A number of synthetic routes for producing polycarbonates have been described. During this process phenol is removed by distillation and recycled by transesterification with DMC to afford DPhC which is employed again in the polycarbonate production process .

6.15.1.2 6.15.1.2.1

Two Sulfur Functions Dithiocarbonates by [3,3]-sigmatropic rearrangement

Alkylxanthate undergoes a thermal [3,3]-sigmatropic rearrangement to form the dithiocarbonate, which is the starting material for a novel rearrangement of allylic thionitrites to thioepoxides (Equation (10)) . R1

S R3

6.15.1.2.2

S

ð10Þ

SMe

Reflux, 7 h

R2

R1

R3

THF

SMe

O

R2 O

1,3-Dithiol-2-ones by xanthogen disulfide-alkyne cycloaddition

1,3-Dithiol-2-ones (cyclic dithiocarbonates) have been prepared in a single-step synthesis from diisopropylxanthogen disulfide and an alkyne in a radical cycloaddition reaction . The method is versatile and provides good yields; in particular, with arene-substituted alkynes, starting materials are commercially available. The radical cyclization is initiated by AIBN (Scheme 6). The scope of the reaction can be extended to some alkenes such as bornene and norbornene . S S

O

S

AIBN

O

S

2

Heat

O

S

.

S R

.

O S +

R

. S

R

R=

*

*

O

S

76–82% S

MeO

* CO2Me

Scheme 6

* HO

*

436

Functions Containing a Carbonyl Group and at Least One Chalcogen

This proven method has been applied to the preparation of an intermediate of molybdopterin, where the needed alkynes are disubstituted, yields are similar to those reactions with monosubstituted alkynes (Equation (11)) . For work-up only flash chromatography is necessary. O O O

S

H

N

AIBN Toluene

N

S

H

N

2 x 1.5 h Reflux 77%

+ S O

S

ð11Þ

O

N

O

O

S S

6.15.1.2.3

Mixed methods

Besides these classical methods some less common synthetic approaches have been published. Benzo-1,3-dithiol-2-ones are important precursors for tetrathiofulvalenes (TTFs) which have been successfully used as building blocks for low-dimensional organic conductors and superconductors. They have been prepared from benzo-1,3-dithiol-2-thiones (Equation (12)) . By the same method a 1,3-dithiol-2-one intermediate has been prepared for the synthesis of a zinc(II) phthalocyanine derivative functionalized with four peripheral substituted TTF units . OTBDPS

OTBDPS

S

Hg(OAc)2

S

DCM, AcOH 85%

S

S S OTBDPS

6.15.1.3

O

ð12Þ

OTBDPS

Two Selenium Functions

An unusal synthesis of Se,Se0 -diphenyldiselenocarbonate has been accomplished by the reaction of dipotassium nitroacetate with benzeneselenyl bromide in 19% yield (Equation (13)) . The product is thermally unstable. K+ _ KO2C

6.15.2

O NO2

+ 2PhSeBr

ð13Þ

MeOH 1 h, 19%

PhSe

SePh

CARBONYL CHALCOGENIDES WITH TWO DISSIMILAR CHALCOGENIDE ATOM FUNCTIONS

6.15.2.1 6.15.2.1.1

Oxygen and Sulfur Functions Thiocarbonates from activated carbonates

A simple and efficient procedure has been developed for a one-pot synthesis of substituted benzothiazine-2,4-diones from thiosalicylic acid and amines. Both functional groups of thiosalicylic acid are reacted and activated, recpectively, with ethyl chloroformate affording the intermediate thiocarbonate in 62% yield (Scheme 7) .

Functions Containing a Carbonyl Group and at Least One Chalcogen O

O CO2H + 2ClCO2Et SH

2Et3N

OEt

O

CHCl3

437

S O

H2N

OEt

62%

O N H S O

OEt

+ CO2 + EtOH

Scheme 7

An alkyl chloroformate has also been employed to form thiocarbonates from thiols for the ‘‘desymmetrization’’ of 2,20 ,6,60 -tetramethoxybiphenyl by a regioselective sulfenylation reaction . This provides an access to C2-symmetric sulfur derivatives. Resolution of 2,20 ,6,60 -tetramethoxy-3,30 -dimercapto1,10 -biphenyl was achieved by conversion to the corresponding dithiocarbonate diastereomers. During the synthesis of potential plant protecting compounds on basis of 2,3-didehydrothiazole2-thione, isobutyl chloroformate has been used to acylate the tautomeric form of the thione catalyzed by lead nitrate affording the corresponding thiocarbonate in 89% yield (Equation (14)) . But

H N

S S

6.15.2.1.2

+ ClCO 2Bui

Cat. Pb(NO3)2

But

N S

DCM, Et3N 89%

OBui

S

ð14Þ

O

Thiocarbonates from alkoxycarbonylsulfenyl chlorides

For synthesis of the two conformationally different ‘‘tetrathiacyclododecino tetraindoles’’ the intermediate 3,30 -bis(methoxycarbonylsulfenyl)-2,20 -biindolyl has been prepared from 2,20 bisindolyl- and methoxycarbonylsulfenyl chloride in excellent yield of 94% (Equation (15)) . Reaction occurs at rt within 2 h and needs no Friedel–Crafts catalyst. OMe O H N N H

S

MeO2CSCl DCM, rt, 2 h 94%

H N

ð15Þ N H

S

O

MeO

6.15.2.1.3

Thiocarbonates from carbonothioic acid salts

As described above, S-methyl O-benzyl carbonothioates with substituted phenyl groups have been prepared by carbonylation of benzyl alcohols with carbon monoxide and sulfur (or carbonyl sulfide) in the presence of DBU followed by esterification using methyl iodide in good yields (Equation (16)) .

438

Functions Containing a Carbonyl Group and at Least One Chalcogen

OH

+ CO + S

O

i. DBU, THF 1 MPa CO 80 °C, 6 h

S

O

ð16Þ

ii. MeI 20 °C, 16 h 89%

6.15.2.1.4

Other methods

Benzimidazo[1,2-c]quinazoline-6(5H)-thiones were prepared by cyclization of 1,2-diaminobenzene with dimethyl 2-isothiocyanatoterephthalate and acylated with ethyl chloroformate according to Equation (17) affording thiocarbonate in 70% yield . O OEt S

N=C=S CO2Me

NH2 + NH2

MeO2C

N i. PriOH

N

ii. ClCO2Et DMF, Et3N 70%

N

ð17Þ

CO2Me

A convenient process for the synthesis of highly functionalized glyoxylic acid derivatives has been accomplished by reaction of n-butylglyoxylate with triphosgene, sodium thioethylate, and benzoic acid, to provide the acetal containing a thiocarbonate moiety with excellent yield of 91% (Equation (18)) . i. (Cl3CO)2CO THF, pyridine ii. NaSEt, Et 2O

O BunO O

iii. Ph-CO 2H THF, DIPEA 91%

O

SEt

O O

BunO

ð18Þ Ph

O O

According to Equation (19) a thiocarbonate is quantitatively formed from methyl 2-thioxo3H-benzoxazole-3-carboxylate with 1,6-dimethyl-2,4-hexadiene in a photochemical reaction . O O S N

OMe S

O

6.15.2.2 6.15.2.2.1

N Photochem. Benzene, 100%

OMe

ð19Þ

O

Other Dissimilar Chalcogenide Functions Oxygen and selenium functions

During the synthesis of ‘‘mucocin,’’ a powerful antitumor ‘‘acetogenin,’’ the 4-hydroxybutenolide terminus is a key intermediate. Its precursor, the selenocarbonate, has been prepared according to Scheme 8 in a yield of 89% . Total synthesis of mucocin was achieved in an analogous way for preparing the selenocarbonate 2 (yield 78%) by using TBDPS protective group and triphosgene instead of phosgene as a carbonyl source . In the synthesis of ‘‘(+)-juruenolide C,’’ a 5-exo-digonal radical cyclization has been applied with a selenocarbonate intermediate 3, which has been prepared in 74% yield in a similar way as described above by using carbonyldiimidazole (CDI) as a carbonyl source .

439

Functions Containing a Carbonyl Group and at Least One Chalcogen O TBDMSO

+ TBDMSO

Se

O BuLi THF

PhSeH 89% Pyridine

O Cl

Cl TBDMSO

Ph

O

TBDMSO

Et3N

Cl

O

OH TBDMS = t-butyl dimethyl silyl

O

Scheme 8 O Se

O

Ph

TBDPSO TBDPS = t-butyl diphenyl silyl

MeO

O

OMe

O 2

O Ph

Se

O O

t Bu2SiH

O O

3

Preparation of 5-selenopentopyranose sugars from pentose starting materials by samarium(II) iodide or (phenylseleno)formate-mediated ring closures is described . Selenocarbonates have been prepared by insertion of selenium into the zinc–carbon bond of arylzinc halides forming corresponding zinc selenoates which react with acyl halides in the presence of HMPA providing selenocarbonates in good yields (Equation (20)) . O MgBr

i. ZnCl 2, THF ii. Se

Se

OMe

ð20Þ

iii. ClCO2Me HMPT 70%

6.15.2.2.2

Oxygen and tellurium functions

Alkyl aryl tellurocarbonates, which are effective precursors of oxyacyl, primary, and secondary alkyl radicals, have been prepared from diphenyl ditelluride and alkyl chloroformate in good yields (Equation (21)) . The same tellurocarbonates can be obtained in yields of 60–96% by palladium-mediated reactions of chloroformates with aryltellurotris(trimethylsilyl)silane (Equation (22)) .

Ph

Te

Te

Ph

i. NaBH4 MeOH, THF ii. ClCO2Me THF, 91%

O MeO

Te

Ph

ð21Þ

440

Functions Containing a Carbonyl Group and at Least One Chalcogen SiMe3 SiMe3

Si Te Ph

+ ClCO 2Me

MeO

Benzene 80%

SiMe3

6.15.2.2.3

O

Pd(PPh3)4

Te

Ph

ð22Þ

Sulfur and selenium functions

A thioselenocarbonate precursor for the synthesis of thioselenofulvalenes, which are strong electron donors, has been prepared in several steps according to the overall Equation (23) . KCNS +

O

+ Cl-Mg

+ Se + EtSCN + CS2 + Tol-SO 2Cl 83%

O

ð23Þ I

S

S

S

Se

O

6.15.3

CARBONYL CHALCOGENIDES WITH A CHALCOGEN FUNCTION AND ONE OTHER HETEROATOM FUNCTION

6.15.3.1

Oxygen and Nitrogen Functions

Carbamates are carbonic acid derivatives containing a carbonyl function directly connected to an alkoxy function and an amino function. They are important for producing pharmaceuticals and polymers, and therefore many preparative methods exist. A review is given in . The formal constitution allows a great deal of variety in the alkoxy component as well as the basic amino function. In general, two synthetic approaches to carbamates can be distinguished: the first method involves a carbonic acid derivative of an alcohol or of a phenol reacting with ammonia or amine and the second one involves carbonic acid derivatives of ammonia or an amine reacting with an alcohol or a phenol.

6.15.3.1.1

Carbamates from chloroformates or phosgene equivalents

Chloroformates are easily prepared using phosgene or phosgene equivalents such as the readily available triphosgene (bis(trichloromethyl)carbonate) . 2-Methyl-2-propyl-1,3-propanediol dicarbamate (Meprobamate), a general sedative, is synthesized by the low-temperature phosgenation of the substituted 1,3-propanediol in an inert medium in the presence of a tertiary amine, followed by conversion of the bischloroformate derivative to the dicarbamate by ammoniation with gaseous NH3. Antipyrine gave consistently higher yields than other tertiary amines (Equation (24)) . i. COCl2 Antipyrine Toluene, CHCl3 OH

OH

ii. NH3 (g)

H2N

O O

O

NH2

ð24Þ

O

2-Cyclohexenyloxycarbonyl chloride has been reacted with 2-hydroxymethylaniline to provide the corresponding carbamate in 76% yield (Equation (25)) .

Functions Containing a Carbonyl Group and at Least One Chalcogen H

Cl

O

OH

+

O

NH2

441

OH

Pyridine DCM

ð25Þ

NH

0 °C to rt 2 h, 76%

O

O

H

(4R,5S)-4,5-diphenyl-2-oxazolidinone has been prepared from (1S,2R)-(+)-2-amino1,2-diphenylethanol and triphosgene (Equation (26)) . It is used for the synthesis of optically active amines because of its high stereoselectivity and easy deprotection by hydrogenolysis after the reaction . The procedure can also be used for preparing 2-oxazolidinones from various 2-aminoethanol derivatives.

+ Ph

H2N

DCM Et3N

O

Ph

HO

Cl3CO

OCCl3

O

Ph

N H

Ph

ð26Þ

O

95% purity via the preliminary deactivation of the acid functionality by condensation of an aminophenylboronic acid with resin-bound diethanolamine followed by treatment of the polymer-supported boronate thus prepared with an isocyanate and mild acidic cleavage from the solid support .

(ii) Additions of amines to isocyanates with formation of cyclic ureas (a) Solution-phase reactions. Reactions of isocyanates with amines, bearing a suitably located additional functional group sensitive to nucleophilic attack, are often followed by the intramolecular reactions of the nitrogen atom of the newly formed urea fragment with formation of five- or six-membered cyclic ureas. These ring closure reactions could be further subdivided into substitution and addition reactions, the former being more widely exploited. This isocyanate addition/intramolecular substitution approach generally uses
- or -amino acids and esters as amine components, and the ring closure step includes intramolecular acylation of the newly formed urea fragment (e.g., Scheme 3). This procedure is most commonly applied to the preparation of fused polyheterocyclic systems , but was also used for the synthesis of monocyclic substituted tetrahydropyrimidinediones , chiral hydantoins , and 5-alkoxyhydantoins .

COOH

HO

COOH

HO R2NCO

NH N H

R1

N reflux acetone/DMSO 30–82%

N H

R1

NHR2 O

O

H

HO

2 N R

N N H

O R1

R1 = H, Me; R2 = Me, Et, n-Pr, Ph

Scheme 3

Ethoxycarbonylhydrazones 8 of aromatic aldehydes and ketones react with 2 equiv. of an isocyanate in triethylamine with formation of intermediates 9, which immediately undergo intramolecular N-acylation/ring closure to give imino-substituted triazinetriones 10 (Scheme 4) .

457

Functions Containing a Carbonyl Group and Two Heteroatoms O

EtO R2 R1

N

R3NCO (2 equiv.)

H N

OEt

N

Et3N, rt

O

15–79%

R1

N O R2

8

O

R3 N

NHR

R1

3

N R2

O

9

O

N

N N R3

R3 O

10 R1 = Me, Ph, 4-ClC6H4, 4-MeC6H4; R2 = H, Me

Scheme 4

On carbamoylation of 2-methylimidazoline, three equivalents of an aryl isocyanate are consumed affording hexahydroimidazo[1,2-c]pyrimidine-5,7-diones in good yields . Intramolecular addition reactions, realized as a second step in one-pot preparation of cyclic ureas, include: (a) addition to a carbonyl group ; (b) addition to a thiocarbonyl group followed by H2S elimination ; (c) addition to a carboncarbon double bond of enamines ; (d) addition to a carbonnitrogen double bond of imines , isothiocyanates , oximes , diazo compounds or methyleneamines, generated in situ by retro-Mannich reaction of hexahydro-1,3,5-triazines ; (e) addition to a carboncarbon or carbonnitrogen triple bond. The latter could further be followed by another cyclization reaction or rearrangement thus providing access to highly substituted polyheterocyclic systems. (b) Solid-phase synthesis. There are two major approaches to the solid-phase synthesis of heterocycles with a urea fragment. The first is based on the direct construction of the desired heterocyclic ring on the solid support using the isocyanate addition/cyclization procedures, described above for solution-phase synthesis, followed by simple cleavage from the resin. The representative examples of this approach include: preparation of quinazoline-2,4-diones from resin-bound 2-aminobenzoates , 1,3-disubstituted uracils and 1,3,5-triazine-2,4,6-triones from
-amino esters, 1,3,5-triazine-2,4-diones from resin-bound guanidines , and trisubstituted triazinobenzimidazolediones from polymer-supported 2-iminobenzimidazoles . In the second approach, the acyclic urea fragment is constructed while on a solid support. The subsequent cleavage from the resin releases a reactive functional group (most commonly, carboxylic group), which intramolecularly reacts with the nitrogen atom of the urea unit affording the corresponding cyclic ureas. This approach was successfully used for synthesis of functionalized hydantoins , spiro-hydantoins , tetrahydrouracils , and 1,2,4-trisubstituted urazoles .

(iii) Self-condensation and cycloaddition reactions of isocyanates (a) Dimerization and trimerization reactions. Catalytic cyclodimerization and cyclotrimerization reactions of isocyanates with formation of symmetrical 1,3-diazetidine-2,4-diones 11 or isocyanurates 12, respectively, are well known (Scheme 5). The direction of the cyclocondensation depends predominantly on the catalyst and the reaction conditions used.

O

O R R N

N R

RNCO O

O 11

Scheme 5

N

N N R 12

R O

458

Functions Containing a Carbonyl Group and Two Heteroatoms

A wide variety of catalysts for high-yielding trimerization of isocyanates includes fluoride salts , tricyclic proazaphosphatrane and its derivatives , potassium or sodium piperidinedithiocarbamate under conventional or microwave heating , sodium p-toluenesulfinate , trialkyl amines , tetrasulfido tin complexes , and transition metal complexes e.g., CpCo(PPh3)Me2, in supercritical carbon dioxide . Even minor changes in the catalyst composition can affect the product distribution: thus, self-condensation of PhNCO in the presence of the oxoniobocene complex [Cp*2Nb(O)OMe] resulted in exclusive formation of triphenyl isocyanurate, whereas the [Cp*2Nb(O)H]-catalyzed reaction gave a mixture of dimerization and trimerization products with the former predominating . The exclusive or predominant formation of 1,3-diazetidine-2,4-diones 11 occurs either on heating without a catalyst or under catalysis with pyridine or 2- or 4-picolines under high pressure . In the latter case, the selectivity of the dimerization increases with the increase in pressure or in amount of the pyridine catalyst, whereas polar solvents, such as acetonitrile, favor the trimeric product. The predominant dimerization of phenyl isocyanate was also observed when 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) was used as a catalyst . The reaction of tungsten hexachloride with excess of ethyl isocyanate in dichloroethane led to insertion of three isocyanate molecules into one of the tungstenchlorine bonds furnishing the tungsten complex WCl4[(EtNCO)3Cl], which on hydrolysis gave isocyanurate 12 (R = Et) . Self-condensation of isocyanates under aqueous (aq.) basic conditions affords acyclic symmetrical ureas. Thus, heating 3-alkoxyphenyl isocyanates in aq. NaOH gave the corresponding N,N0 -bis(3-alkoxyphenyl)ureas in 72–83% yields . Aromatic isocyanates were readily converted into symmetrical 1,3-diaryl ureas in 85–95% yields in aq. pyridine at 20
C . (b) Other cycloaddition reactions of isocyanates. SbCl5-Catalyzed 1,3-dipolar cycloaddition of isocyanates with
-chloro-substituted azo compound 13 afforded the corresponding triazolonium hexachloroantimonates 14 in moderate yields (Equation (2)) (where TMSNCO indicates trimethylsilyl isocyanate) , whereas 1,3-dipolar cycloaddition of isoquinolinium arylimides, generated in situ from N-(arylamino)isoquinolinium halides, gave the corresponding triazoloisoquinolones in 87–99% yields .

Me Cl

i. SbCl 5, CH2Cl2,

Me N

N

–60 °C

Ar

Me

+ Me N N N Ar R

ii. RNCO 42–68%

–

SbCl6

ð2Þ

O 14

13

R = H (from TMSNCO), t-Bu, Ph

Ar = 2,4,6-Cl3C6H2

Heating phenyl isocyanate with nonsymmetrical azines 15 in xylene triggered two consecutive 1,3-dipolar cycloaddition reactions yielding heterocycles 16 with three fused five-membered rings (Equation (3)) . 1,3-Dipolar cycloaddition of phenyl isocyanate to
-imino thioamides occurs with sulfur elimination affording 4-amino-1,3-dihydroimidazol-2-ones . O

Ph R H2C

N

OMe

C

N Me Me 15

N

PhNCO Xylene Reflux

N N

Me Me

OMe

ð3Þ

R 16 R = Me (64%), Et (68%)

The in situ 1,3-dipole generation via thermal or palladium-catalyzed ring opening of threemembered heterocycles, such as functionalized aziridines , bicyclic aziridines , or oxaziridines , in the presence of isocyanates

459

Functions Containing a Carbonyl Group and Two Heteroatoms

presented a convenient method for regioselective preparation of substituted imidazolin-2-ones, pyrazolo[1,2-a][1,2,4]triazolones and 1,2,4-oxadiazolidin-3-ones, respectively. A similar azetidine ring opening/isocyanate cycloaddition of 2-vinyl azetidines under palladium catalysis or of 2-azabicyclo[2.2.0]hex-5-enes afforded the corresponding vinylic or azetidine-fused tetrahydropyrimidin-2-ones in moderate to excellent yields. Chiral 2-alkenyl dihydrooxazoles 17 (X = O) react with 2 equiv. of aryl and arylsulfonyl isocyanates to give nonracemic dihydropyrimidone derivatives 18 (Scheme 6) via asymmetric hetero-Diels–Alder reaction followed by the addition of a second molecule of the isocyanate to the cycloadduct . The thia analogs 18 (X = S) were obtained in the similar reactions of 17 (X = S) with tosyl isocyanate; however, cycloaddition with less reactive phenyl isocyanate afforded 1:1 adduct 19 as the sole product .

O

R1

R1

R3HN

N X

R3

2R3NCO

N

X

R2

R2

(X = S, R1 = Ph, R2 = H)

R1

= Me, Et, Ph;

R2

Ph O

N

S

55%

17

18 X = O;

N

PhNCO

25–94%

O

N

Ph

19

= Et;

X = S; R1 = Ph; R2 = H, (i-Pr)3SiOCH 2 R3 = Ph, 4-BrC6H4, Ts, etc.

Scheme 6

Other examples of hetero-Diels–Alder cycloaddition reactions with isocyanates include the preparation of benzimidazolotriazinones and benzothiazolotriazinones from the corresponding N-(2-heteroaryl) arylimines and of imidazo[5,1-d]-1,2,3,5-tetrazin-4-one (temozolomide) and analogs from 5-diazoimidazole-4-carboxamide . [2+2+2]-Cycloadditions of N-trimethylsilyl imine 20 with various isocyanates afforded unsymmetrical 1,3,5-triazine-2,4-diones 21 (Scheme 7) in 75–96% yields . Importantly, two different isocyanates could be added stepwise allowing for introduction of different substituents on N-1 and N-3 atoms of the cycloadducts. Analogous [2+2+2]-cycloaddition of 3-aryl-3,4-dihydroquinazolines with 2 equiv. of phenyl isocyanate gave the corresponding quinazolinotriazinediones . CH2OTBDMS

CH2OTBDMS

CH2OTBDMS CH2OTBDMS

R2NCO

R1NCO

N

TMS

R1

N

N

N O TMS

O N TMS

20

75–96%

R1

HN O

N N R1

R2 O

21

Scheme 7

Benzotriazolyl-substituted iminium chloride undergoes [1+2+2]-cycloaddition with 2 equiv. of phenyl isocyanate to give, after quenching with an appropriate nucleophile, functionalized hydantoins in moderate yields . Conjugated heteroarylvinyl iminophosphoranes react with alkyl or phenyl isocyanates via the azaWittig-type reaction and formation of carbodiimide intermediates to afford heteroarylmethylidenesubstituted imidazoline-2,4-diones in moderate yields . A similar approach was used for the solid-phase synthesis of 2-imino-4-oxo-1,3,5-triazino[1,2-a]benzimidazoles from resin-bound 2-benzimidazolyl iminophosphoranes .

460 6.16.1.1.2

Functions Containing a Carbonyl Group and Two Heteroatoms Reactions with metal cyanates

Reactions of primary amines with sodium or potassium cyanates (Equation (4)) represent the most common method for the preparation of monosubstituted ureas. As an amine component, benzylic amines , anilines , sterically constrained primary amines ,
-amino acids , -amino acids , and amino sugars were successfully used. The kinetics of N-carbamoylation of
-amino acids with potassium cyanate were studied in detail . O RNH2

+

R

MOCN

N H

(M = K, Na)

ð4Þ

NH2

Secondary aromatic amines , hydroxylamines , and even azaheterocycles, such as 4,5-disubstituted 2,4-dihydro-1,2,4-triazol-3-ones , were also reacted with potassium cyanate to afford the corresponding urea derivatives. When the amine component has a suitably located carbonyl group, the latter undergoes intramolecular condensation with the newly formed urea fragment . The reaction of KOCN with haloalkyl acrylates and methacrylates 22 gave the corresponding symmetrical ureas 23 (Equation (5)) . The presence of water is required to suppress the trimerization of the intermediate isocyanates. R

R

KOCN

O(CH2)nX

H2C O

O(CH2)nNH

H2C

aq. MeCN

O

Bu4 NBr

22

69–85%

CO 2

ð5Þ

23 R = H, Me; n = 6, 8; X = Cl, Br

Treatment of acyl or sulfenyl chlorides with silver cyanate in ether or aromatic solvents is a convenient approach to in situ generation of isocyanates which are unstable and/or not readily available. The subsequent addition of amines , N-alkoxyamines , or hydrazines allows for the preparation of the corresponding functionalized ureas and sulfenyl carbazides.

6.16.1.1.3

Carbonylation of amines

A convenient approach to the conversion of primary and secondary amines into symmetrical ureas is the catalytic oxidative carbonylation of the amines with CO/O2 (Equation (6)). A wide variety of catalysts has been found effective for this reaction, including selenium compounds , manganese-based catalysts , resin-immobilized gold , Pd/H2SO4-modified ZrO2 , sulfur , polymersupported palladiumcopper catalyst , PdI2/KI catalytic system , and palladium methoxycarbonyl complexes in the presence of CuCl2 . Electrocatalysis has also been applied . Primary aromatic amines and secondary aliphatic amines are generally less reactive than primary alkylamines, allowing for the preparation of unsymmetrical ureas by oxidative carbonylation of primary alkylamines in the presence of excess of a less reactive amine . R1R2NH

+

R3R4NH

CO Catalyst or ∆

O R1

N R2

N R4

R3

ð6Þ

High-pressure Se-catalyzed carbonylation of amines and diamines with [11C] carbon monoxide provided access to 11C-labeled cyclic and symmetrical acyclic ureas . Treatment of N,N0 -di(t-butyl)diaziridinone with Ni(CO)4 under CO atmosphere resulted in CO insertion into the NN bond giving the ring expansion product, symmetrical N,N0 -di(t-butyl)diazetidinedione, in 75% yield .

Functions Containing a Carbonyl Group and Two Heteroatoms

461

Instead of oxygen, iodine could be used as an oxidant. Thus, tungsten-catalyzed carbonylation of aliphatic primary and secondary amines and diamines in the presence of iodine furnished a series of acyclic and cyclic ureas . This reaction is compatible with acid-sensitive and fluoride-sensitive functional groups. A nitroarene, such as 3-(trifluoromethyl)nitrobenzene, was also used as an oxidant for Se-mediated conversion of primary alkylamines into symmetrical 1,3-dialkyl ureas . The ability of carbon monoxide to reduce nitroarenes to the corresponding anilines has been exploited in the preparation of 1,3-diaryl- and 1-aryl-3-cycloalkyl ureas . Selenium is the most common catalyst for this process, although a polymer-supported rhodium catalyst has also been applied . In these reactions the nitro compound acts as both the reagent and an oxidant. The use of toxic carbon monoxide could be avoided by replacing it with CO2. Thus, 1,3-dialkyl ureas and 2-imidazolinones were successfully prepared from the corresponding amines or diamines and CO2 at 80
C using the Ph3SbO/P4S10 catalytic system . Trisubstituted ureas were also synthesized under these conditions in moderate yields, but the attempts to prepare a tetrasubstituted urea, other than tetramethylurea, failed. This shortcoming was later overcome by carrying out the reaction in the presence of carbon tetrachloride and 1,8-bis(dimethylamino)naphthalene . Purging CO2 into a mixture of a primary aromatic amine and DBU in pyridine or tetrahydrofuran (THF) followed by addition of the trimethylamine–sulfur trioxide complex as a dehydrating agent gave the corresponding 1,3-diaryl ureas in 23–87% yields . The analogous reaction of ammonia with carbon dioxide with removal of water using water-selective membranes allowed for the large-scale preparation of unsubstituted urea . Heating primary aromatic or aliphatic amines with ethyl acetoacetate at 180
C in the presence of the commercially available zeolite, HSZ-360, led to carbonylative dimerization of the amines affording symmetrical 1,3-diaryl or 1,3-dialkyl ureas as the sole reaction products . The reaction presumably occurs via the intermediate formation of the corresponding acetoacetamide, which undergoes CC bond cleavage on further reaction with an amine.

6.16.1.1.4

Substitution reactions of amines with phosgene and its equivalents

(i) Reactions of amines with phosgene Despite its toxicity, phosgene is still utilized, although to a lesser degree than other carbonic acid derivatives, for the conversion of amines into ureas (Equation (7)). The reaction generally takes place in inert solvents (toluene, dichloromethane, THF) at 0–5
C in the presence of a base (aq. NaHCO3, aq. NaOH, triethylamine, etc.). O R1R2NH

+

R3R4NH

+

COCl2

R1

N R2

N R4

R3

ð7Þ

The reactions of phosgene with 2 equiv. of an amine were used for the synthesis of a variety of symmetrical ureas, including N,N0 -carbonylbis(azoles) and cyclic ureas, such as 4,5-diaminoimidazol-2-ones , imidazolidin-2-ones and their fused analogs , tetrahydropyrimidin2-ones , and hexahydroazepin-2-ones . More useful, however, is the synthesis of unsymmetrical ureas by consecutive treatment of phosgene with two different amines with in situ formation of an isocyanate intermediate. A combination of two aromatic amines , two amino acids , or an aromatic or heterocyclic amine and O-alkyl hydroxylamine were all successfully used. 14C-Labeled phenylureas bearing photoactive azido and diazine groups were also prepared by this procedure . The reaction with phosgene was also employed in the solid-phase synthesis of functionalized N-carbamoyl indolines .

462

Functions Containing a Carbonyl Group and Two Heteroatoms

(ii) Reactions of amines with carbamoyl chlorides Reactions of carbamoyl chlorides with amines (Equation (8)) are comparatively seldom used for the urea synthesis, probably due to a limited range of available carbamoyl chlorides. O R1R2NH

+

R1

R3R4NCOCl

N R2

N R4

R3

ð8Þ

Dialkyl and alkyl aryl carbamoyl chlorides were successfully used for carbamoylation of azaheterocycles, such as triazoles , oxazolidinones and tetrazolinones , arylhydrazines , and O,O0 -polyoxyethylene bis(hydroxylamine)s , the latter being dicarbamoylated. In contrast, treatment of O,O0 -polyoxyethylene bis(hydroxylamine) with N-carbazolylcarbonyl chloride gave exclusively the monocarbamoylation product, albeit in a moderate yield . Carbamoylation of pyridines affords the corresponding N-carbamoylpyridinium halides ; however, when
-chloroformyl arylhydrazines 24 are used as the reactants, further attack of the free amino group at the 2-position of the pyridine ring occurs to afford [1,2,4]triazolo[4,3-a]pyridine-3-ones 25 (Equation (9)) . The analogous cyclization reaction was observed with isoquinoline and pyridazine . Pyrimidine, however, was unreactive under the reaction conditions, whereas 1,3,5-triazine, thiazole, and 1,4,5,6-tetrahydropyrimidine underwent ring opening of the original heterocycle to afford functionalized 2,4-dihydro-1,2,4-triazol-3-ones in good yields. O Ar

100 °C

+

N Cl NH2

N

12 h

N

75–84%

excess

24

N Ar

N

ð9Þ

O 25

Ar = Ph, 4-ClC6H4, 4-MeC6H4

Carbamoylation of N-alkyl hydroxylamines with N-cyano-N-arylcarbamoyl chlorides followed by intramolecular addition of the N-hydroxy group to the nitrile furnished the corresponding 1,2,4-oxadiazol-3-ones in 93–98% yields . Analogous tandem carbamoylation/intramolecular cyclization procedure was used for preparation of thiatetraazaindenones and -fluorenones from mercapto-substituted triazoles and benzimidazoles, respectively .

(iii) Reactions of amines with chloroformates Chloroformates, bearing two good leaving groups of different nucleofugicity, represent convenient reagents for step-by-step CO-linking of different amines (Scheme 8) and preparation of unsymmetrical ureas without isolation of the intermediate carbamates.

O

O 1 2

R R NH

+

Cl

R1 OR3

N R2

R4R5NH

OR3

O R1

N R2

N R5

R4

Scheme 8

The most widely used are phenyl and 4-nitrophenyl chloroformates, although some alkyl and chloroalkyl chloroformates are also applied. This approach was successfully used for the preparation of di- and trisubstituted ureas , N-carbamoyl amino esters , and N-arylcarbamoyl aminopyrazoles and indolines . The procedure was also applied to solidphase synthesis of functionalized ureas .

Functions Containing a Carbonyl Group and Two Heteroatoms

463

When a substrate molecule has two amino groups of different reactivity, intramolecular cyclization can occur. Thus, heating pyrazolyl hydrazides 26 with trichloromethyl chloroformate gave pyrazolotriazinediones 27 (Equation (10)) , whereas condensation of
-hydrazono selenamide with methyl chloroformate afforded selenated 1,2,4-triazine-3-one in 49% yield .

R O

R H N

N N H

O

+

N H

O

Cl

Ar

CCl3

Toluene

N

Reflux, 1 h 53–68%

O

O

N

26

N Ar

NH

ð10Þ

27

R = H, Cl, Br, NO2 Ar = Ph, 2-MeC6H4, 3-ClC6H4

(iv) Reactions of amines with carbamates and thiocarbamates Carbamates represent the carbonic acid derivatives most widely used in the urea synthesis and are generally prepared by partial aminolysis of chloroformates (see Scheme 8). O-Phenyl and O-tbutyl carbamates are the most popular, the latter being readily available from amines and (BOC)2O. Aminolysis of carbamates (Equation (11)) usually requires the presence of a base (triethylamine, DBU, NaHCO3, etc.) and, when necessary, can be promoted by addition of chlorosilanes or by heating over -Al2O3 . O R1R2NH

+

R3

N R4

O X

R5

R1

N R2

N R4

R3

ð11Þ

X = O, S

The reaction is tolerant to a wide variety of the functional groups on both the carbamate and the amine reactants allowing for the preparation of multiply functionalized ureas, including: acryloyl ureas , hydroxy-substituted ureas , polyfluorinated ureas , arylsulfonyl and heteroarylsulfonyl ureas , carbamoyl diamino acids , N-carbamoyl nucleosides , carbamoylamino glycosides and N-carbamoyl piperidines , piperazines , indolines , dihydroquinolines , and dihydrophthalazines . The groups sensitive to the transformation include some amino protecting groups, such as N-benzoate and N-phenoxycarboxylate . The carbamate aminolysis has also been applied to the solid-phase preparation of N-carbamoyl dihydroquinolinones , N-carbamoyl guanidines , oligoureas , and libraries of di- and trisubstituted ureas . On treatment with amines, cyclic carbamates, such as 2-oxazolidinones or 1H-thieno[2,3-d][1,3]oxazine-2,4-diones , undergo aminative ring opening to afford hydroxy- or carboxy-functionalized ureas, respectively. When a reactive amino or imino function is already present in the carbamate or activated in situ by deprotection, the intramolecular carbamoylation can occur allowing for access to variously substituted hydantoins , optically active polycyclic ureas , triazinediones , and fused tetrazinones . Cyclic ureas could also be prepared by intermolecular carbamoylation if the carbamate and/ or amine component have additional reactive functional groups. Thus, hydantoins 29 (Equation (12)) and their dehydro derivatives were prepared by condensation of N-BOC amines 28 having the

464

Functions Containing a Carbonyl Group and Two Heteroatoms

activated
-position with imines and nitriles , respectively. Cyclocondensation of
,-unsaturated -amino acids or their esters with carbamates afforded uracil derivatives , whereas the reaction of dihydrobenzodiazepinethione with ethyl carbazate gave fused triazolobenzodiazepinones in moderate yields . Pyrazolo[1,5-d][1,2,4]triazinones were prepared via the analogous cyclocondensation of 5-acylpyrazolyl-1-carboxylates with phenylhydrazine . R1 R R2

OMe

1

N

+

BOC

R3

s-BuLi THF or Et2O

N

–78 °C 22–92%

28

R2

R3

N

N OMe

O

ð12Þ

29

R1 = Ph, R2 = 4-MeOC6H4 R1 = benzotriazol-1-yl, R2 = PhCH2 R3 = Ph, 4-MeOC6H4, 2-furyl, etc.

Aminolysis of S-methyl alkylthiocarbamates with primary or secondary alkyl and cycloalkyl amines in acetonitrile , or with primary sulfonamides in toluene in the presence of DBU , gave the corresponding ureas and sulfonylureas in 60–89% yields without racemization. Although benzamide and thiobenzamide were unreactive under these conditions, aryl-substituted ureas were prepared in 81–100% yields by treatment of thiocarbamates with generated in situ aniline carbanions . Aminolysis of S-allyl N-acylthiocarbamates with a variety of amines in benzene-water twophase system or with phenylhydrazine in benzene afforded the corresponding acyl ureas and acyl semicarbazides, respectively. Thermolysis of N-aryl carbamates at 230–240
C produces the corresponding symmetrical 1,3-diarylureas in 42–97% yields .

(v) Reactions of amines with ureas (a) Preparation of acyclic ureas via disubstitution of symmetric ureas with amines. Microwave irradiation of a mixture of an aromatic amine or phenylhydrazine with unsubstituted urea afforded the corresponding symmetrical ureas in moderate-to-good yields (Equation (13)) . The addition of a suitable energy-transfer solvent, such as N,N-dimethyl acetamide, to the reaction mixture resulted in significant improvement in the product yields . Primary aliphatic amines and 2-aminopyridines reacted in a similar manner. O RNH2

H2N

O

Microwave

+

NH2

40–90%

RHN

NHR

ð13Þ

R = alkyl, aryl, 2-pyridyl, PhNH

However, of all the symmetrical ureas, commercially available, easily handled, crystalline N,N0 -carbonyldiimidazole (CDI) is the most widely used as a phosgene equivalent. Significantly lower reactivity of an N-carbamoylimidazole, formed after substitution of one imidazolyl group with an amine, compared to CDI itself allows one to carry out the disubstitution consecutively using two different amines or their analogs. This approach was applied in the solution-phase synthesis of optically active dipeptides , N-carbamoyltetrahydropapaverines and 4-hydroxysemicarbazides , and in the solid-phase synthesis of unsymmetrical polyfunctional 1,3-diaryl ureas . Although N-carbamoyl imidazoles, formed from secondary amines and CDI, were found to be unreactive toward coupling with secondary amines, these intermediates could be activated by their conversion into the corresponding imidazolium salts , thus making this approach suitable for the preparation of tetrasubstituted ureas.

465

Functions Containing a Carbonyl Group and Two Heteroatoms

Instead of CDI, 1,10 -carbonylbis(benzotriazole) was used for preparation of tetrasubstituted ureas (no activation is required in this case) and for solution- and solid-phase synthesis of dipeptides . (b) Preparation of acyclic ureas via monosubstitution of ureas with amines. Condensation of unsubstituted urea with a sterically hindered secondary amine in a strongly acidic medium or with a heteroaromatic amine, such as pyrazole, under thermal conditions results in substitution of only one of the urea amino groups providing products of the general formula R1R2NCONH2. On treatment of N-phenylurea with a variety of amines, the unsubstituted amino group of the urea is cleaved, thus allowing access to a series of 1,3-di- and trisubstituted ureas . The same products could be prepared by reaction of 1,3-diphenylurea with amines . Analogously to the second step of the CDI aminolysis, reaction of independently prepared N-carbamoyl imidazoles with amines leads to the substitution of the imidazolyl moiety with the amino group . Similarly, heating resin-bound 1-carbamoyl-1,2,3-benzotriazole with primary or secondary amines results in the nucleophilic displacement of the benzotriazole moiety releasing the newly formed unsymmetrical urea in the solution . (c) Preparation of cyclic ureas. The most widely used procedure for the preparation of cyclic ureas via the substitution pathway is the condensation of urea or its derivatives with diamines. Unsubstituted urea or CDI are generally used as phosgene equivalents. This approach was applied to the preparation of 2-imidazolidinones , 2-benzimidazolones , tetrahydropyrimidin-2-ones , hexahydroazepin-2-ones , hexahydro-1,3,6-triazocin-2-one , and macrocyclic ureas . A series of functionalized hydantoins were synthesized from the corresponding resin-bound 1,2-diamines . Instead of two amino groups, their analogs, such as amide , hydrazine , or amidrazone moieties, can participate in the reaction. If a second amine, used for the double aminolysis of CDI, features a suitably located carboxylic group, the in situ intramolecular cyclization of the newly formed urea can occur giving, for example, fused imidazolidinediones . The similar intramolecular cyclization after formation of the urea fragment was used for solution-phase and solid-phase synthesis of 3-aminohydantoins and 3-aminodihydrouracils.

(vi) Reactions of amines with carbonates and thiocarbonates (a) Preparation of acyclic ureas. Similarly to reactions of ureas with amines, aminolysis of carbonates (Scheme 9) could be carried out by consecutive introduction of two different amines or their analogs allowing for access to unsymmetrical ureas and their derivatives. O

O R1R2NH

+

R3X

R1 XR3

N R2

R4R5NH

XR 3

O R1

N R2

N R5

R4

X = O, S

Scheme 9

Bis(trichloromethyl) carbonate, or triphosgene, is the most widely exploited. Using the coupling reaction with triphosgene, ureas derived from two different amino acids , as well as 1-aryl-3,3-dialkyl ureas , glucopyranosylureas ,
-ureido alkylphosphonates , carborane-substituted ureas , ureapeptoid peptidomimetics , and urea-functionalized porphyrins were all successfully prepared. This approach has also been applied to the solution-phase synthesis of tri- and tetrasubstituted ureas from polyethylene glycol-bound amines and to solid-phase synthesis of peptide C-terminal semicarbazones .

466

Functions Containing a Carbonyl Group and Two Heteroatoms

Other symmetrical carbonates, such as dimethyl carbonate , diphenyl carbonate , cyclic ethylene carbonate and bis(1-cyclohexenyl) carbonate , as well as unsymmetrical diaryl carbonates were also used. Nitrophenyl carbonates were applied in the solid-phase synthesis of various ureas and azapeptides . Although di(t-butyl) carbonate is known to react with amines directly to give N-BOC-protected derivatives, under catalysis with 4-(dimethylamino)pyridine (DMAP) it reacts with a second equivalent of an amine to give the corresponding ureas. This procedure was successfully applied to primary aromatic , primary aliphatic amines and resin-bound anilines ; however, with secondary amines only N-BOC protection was observed . The condensation of primary alkylamines with S,S-dimethyl dithiocarbonate in methanol or without solvent at 60
C gave 1,3-dialkyl ureas . Aromatic and sterically hindered alkylamines are unreactive, whereas dialkylamines give only monosubstituted products i.e., thiocarbamates. (b) Preparation of cyclic ureas. Condensation of carbonates with diamines leads to the formation of cyclic ureas if the diamine structure allows for nonconstrained ring closure. This procedure has been used for the preparation of benzimidazolones in solution and on the solid support , quinazoline-2,4-diones , and macrocyclic carborane-substituted ureas . Low-valent titanium-induced carbonylative dimerization of aryl imines in the presence of triphosgene gave substituted imidazolin-2-ones , which were also prepared via DMAP-catalyzed carbonylative cyclization of 1,2-diamines with BOC2O . Condensation of S,S-dimethyl dithiocarbonate with appropriate diamines afforded a series of imidazolin-2-ones, tetrahydropyrimidin-2-ones, and 2-quinazolinone in moderate to good yields .

6.16.1.1.5

Oxidation of thioureas and related compounds

Both acyclic and cyclic thioureas were readily converted into the corresponding ureas (Equation (14)) on treatment with bismuth nitrate pentahydrate in acetonitrile at reflux or in phosphate buffer at 20
C . The reaction is chemoselective: although thioamides are also oxidized, thiono esters and thioketones are essentially unreactive. Inexpensive, stable, and commercially available Oxone could also be used as an oxidant ; however, in this case the excess of the reagent is required and a poorer chemoselectivity is observed. S R1

N R2

N R4

R3

Oxidant

O R1

N R2

N R4

R3

ð14Þ

Oxidation of 1,3-di- and trisubstituted thioureas was also carried out using sodium metaperiodate, sodium chlorite, and ammonium persulfate in water , whereas N-aroyl ureas were prepared via the oxidation of thioureas with bromine in chloroform (Hugershoff reaction) . Potassium iodate (KIO3) was found to be a convenient reagent for the preparation of N-aroyl ureas , N-acylated bis(urea)s , and N,N0 -diacyl semicarbazides from the corresponding thiocarbonyl analogs. Trisubstituted glucopyranosyl thioureas were readily oxidized with excess of yellow HgO ; the disubstituted analogs, however, gave exclusively bicyclic isoureas. There are few procedures specific for oxidation of cyclic thioureas. These include oxidation with mercury(II) acetate, used for the preparation of 1,3-diacylimidazolidin-2-ones , and oxidation with 30% hydrogen peroxide in aq. NaOH, used in synthesis of six-membered cyclic ureas . Tetrazolinethiones were oxidized to tetrazolinones using unsubstituted oxirane or 2-alkyl epoxides as oxidants .

6.16.1.1.6

Reactions of amines with amides and other carboxylic acid derivatives

Ruthenium-catalyzed carbamoylation of dialkylamines or primary aromatic amines with formanilides at 165
C give the corresponding unsymmetrical diand trisubstituted ureas in high yields. For reaction with anilines, unsubstituted formamide could

467

Functions Containing a Carbonyl Group and Two Heteroatoms

also be used. Although simple alkyl and cycloalkyl amides are unreactive,
-polychloro- or
-polynitro-substituted aliphatic amides readily undergo -elimination to give intermediate isocyanates, which on trapping with ammonia or primary amines afford mono- and disubstituted ureas, respectively (Scheme 10) . O

O R1

N H

R3R4NH

∆

R2

R2

R2NCO

N H

–R1H

N R4

R3

R1 = CCl3, O2NCCl2, MeC(NO2)2

Scheme 10

Curtius rearrangement of acyl azides also produces the intermediate isocyanates as urea precursors. The starting acyl azides are usually generated in situ by one of the following methods: (i) reaction of a carboxylic acid with diphenylphosphoryl azide in the presence of a base ; (ii) from acyl chlorides and sodium azide ; or (iii) oxidation of acyl hydrazides with HNO2 . This approach has also been applied to the synthesis of N,N0 -disubstituted ureas from heterocyclic and aliphatic carboxylic acids and resin-bound amines .

6.16.1.1.7

Miscellaneous reactions

(i) From carbodiimides Hydrolysis of carbodiimides produces the corresponding ureas , whereas their heterocyclization with diaryl nitrones or 2-(bromomethyl)acrylic acid yields polysubstituted 1,2,4-triazolin-3-ones and 5-methylidenetetrahydropyrimidine-2,4-diones, respectively.

(ii) Heterocycle ring–ring interconversions Variously substituted 1,2,4-triazol-3-ones were prepared by ring opening/recyclization of 2-amino-1,3,4-oxadiazoles or 5-amino-1,2,4-oxadiazoles (Equation (15)) in the presence of a primary amine. The rearrangement of arylhydrazones of 3-benzoyl-5-amino-1,2,4-oxadiazoles, however, occurs differently with formation of ureidosubstituted 1,2,3-triazoles . Ph

H

N R1

O

N

+

R2NH2

R1 = NH2, NHMe, NMe2

MeOH 57–60%

Ph N

hν

O

N R2

N

ð15Þ

R2 = H, Me, n-Pr, n-Bu, NH2

Heating 3-(2-oxopropyl)benzothiazol-2-ones with excess of a primary amine in HClO4 affords 1-(2-mercaptoaryl)imidazolin-2-ones, readily oxidizable in air to the corresponding disulfides . Oxidative rearrangement of 3-arylimino-2-indolinones occurs with the ring expansion to give quinazoline-2,4-diones .

(iii) Oxidation Purines and xanthines are readily oxidized to the corresponding 8-oxo derivatives with dimethyldioxirane or bacteria , whereas oxidation of benzimidazolium salts and their N,N0 -polymethylene-bridged analogs in air affords the relevant benzimidazolones

468

Functions Containing a Carbonyl Group and Two Heteroatoms

in high yields . Treatment of amidines with (diacetoxyiodo)benzene yields either 1,3-disubstituted ureas or trisubstituted acylureas depending on the reaction conditions .

6.16.1.1.8

Preparation of carbamoyl azides

The early review on carbamoyl azides indicated three preparation methods, which are still the ones most commonly used: (a) reaction of carbamoyl chlorides with sodium azide; (b) addition of hydrazoic acids to isocyanates; and (c) oxidation of semicarbazides with HNO2. Since this review, only few reports on synthesis of the title compounds have appeared. The reaction of carbamoyl chlorides with sodium azide usually occurs under very mild conditions (aq. acetone, 0–20
C) with carbamoyl chlorides being used as such or prepared in situ from the corresponding amine and phosgene . Treatment of chloroformyl and
-chloroalkyl isocyanates with excess of hydrazoic acid resulted in both addition to the isocyanate moiety and substitution of the chlorine atom with the azido group affording the corresponding diazido compounds, whereas with -chloro-functionalized isocyanates no substitution reaction was observed . The isocyanate reactant can also be generated in situ by addition of hydrazoic acid to acyl ketenes accompanied by nitrogen elimination or by Curtius rearrangement of acyl azides . Instead of unstable hydrazoic acid, its derivatives, such as trimethylsilyl azide or triarylbismuth diazides could be used; however, in these reactions the mixtures of products are usually obtained with the product distribution depending on the reaction conditions. Other methods for synthesis of carbamoyl azides include oxidation of aldehydes with pyridinium chloroformate in the presence of sodium azide and reaction of carboxylic acids with the Vilsmeier salt followed by treatment with sodium azide . The latter approach is high-yielding and applicable to the preparation of a wide variety of carbamoyl azides, including optically active substrates.

6.16.1.2 6.16.1.2.1

Carbonyl Derivatives with One Nitrogen and One P, As, Sb or Bi Function Carbonyl derivatives with one nitrogen and one phosphorus(III) function

The most common procedure for the preparation of carbamoyl phosphines is based on the phosphine addition to alkyl or aryl isocyanates (Equation (16)) . The reaction is tolerant to the presence of thiol , alkylthio , and keto groups, and is applicable both to secondary and primary phosphines. In the latter case, however, double carbamoylation of the phosphine occurs , even for sterically hindered phosphines. R1 P H R2

+

R3 N C O

O R1

P R2

N H

R3

ð16Þ

The bulky analog of PH3, tris(trimethylsilyl)phosphine (tris(TMS)phosphine), gives with isopropyl isocyanate exclusively 1:1 adduct 30, which exists in equilibrium with its (siloxy)imine tautomer 31 (Equation (17)) . Under mild conditions, isocyanates readily insert into the ZrP bond of PH-functionalized zirconocene complexes 32 to afford the corresponding (phosphinoamidato)zirconocenes 33 in 81–85% yields (Equation (18)). The presence of a bulky ligand, such as R1 = 5-C5EtMe4, favors the formation of complexes 33 exclusively as endoisomers (shown), whereas products 33 with less sterically hindered ligands e.g., R1 = 5C5MeH4, were formed as mixtures of endo- and exo-isomers, with exo-isomers predominating . To our knowledge, up to the early 2000s, this reaction represents the only procedure for the preparation of a secondary carbamoyl phosphine in acceptable yields.

469

Functions Containing a Carbonyl Group and Two Heteroatoms

P(TMS)3

O

Et2O, rt

Pri +

N C O

Pri

TMS

3 days

P N TMS TMS

TMS

+

OTMS Pri N P TMS

30

31

R1 O R1 Zr Cl N R3 33

Pentane, rt [R12ZrCl(PHR2)]

R3NCO

+

24 h 81–85%

R3 = i-Pr, Ph

32

ð17Þ

PHR2

ð18Þ

R1 = (η5-C5EtMe4), R2 = cyclohexyl R1 = (η5-C5MeH4), R2 = 2,4,6-Pr3i C6H2

The tertiary phosphine 34, bearing a suitably located boryl group, underwent addition to phenyl isocyanate followed by intramolecular heterocyclization to give the six-membered heterocycle 35 in 63% yield. On heating in benzene or acetonitrile, 35 readily rearranges to the bicyclic heterocycle 36 (Scheme 11) . Ph Ph

Bu BBun2

Ph P

C6H6, rt +

PhNCO Overnight

Ph

+ Ph2P

N O

34

Bun _ MeCN or C6H6 BBu n2 ∆

Ph + Ph2P O

Ph

Bun Bun _ B Bun N Ph 36

35

Scheme 11

Another approach to the synthesis of tertiary carbamoyl phosphines, not including the reaction with isocyanates, is based on carbamoylation of secondary phosphines with carbamoyl chlorides. The only example of such a transformation, reported up to the early 2000s, is carbamoylation of bis(trimethylsiloxy)phosphine 37, which gave the desired derivatives 38 in moderate yields (Equation (19)) . O

Et3N (TMSO)2PH

+

ClCONR2

TMSO

Et2O rt, 2 days

37

52–61%

P NR2 OTMS

ð19Þ

38 R = Me, Et; R2N = morpholino, piperidino

Phenylcarbamoyl phosphine 40 was obtained as the major product of hydrolysis of azaphosphaallene 39 (Equation (20)) . However, the hydrolysis pathway depends dramatically on the nitrogen substituent: for example, replacement of the phenyl group on the nitrogen atom of 39 with a sterically hindered substituent, e.g., t-butyl, results in nucleophilic attack at the phosphorus atom rather than at the carbon, giving quite different sets of products. But But

P C N Ph But 39

6.16.1.2.2

H2O

But O

But

But

P H

N H

Ph

ð20Þ

40

Carbonyl derivatives with one nitrogen and one phosphorus(V) function

As in the synthesis of carbamoyl phosphines (Equation (16)), addition to isocyanates is the most common procedure for the preparation of phosphorus(V)-bearing carbamoyl compounds. As phosphorus reagents, both phosphine oxides and trimethylsilylated phosphites (Equation (21)) can be utilized. The latter reaction was also applied to the synthesis of chiral phosphorus dipeptides . The isocyanate addition can be followed by intramolecular heterocyclization to afford the corresponding phosphaazaheterocycles . Diphosphanyl ketimine oxide 41 serves as a 1,3-dipole in [3+2]-cycloaddition reaction with phenyl isocyanate resulting in formation of azaphospholene 42 in 75% yield (Equation (22)) . The second, also widely used, approach is the substitution reaction of alkoxycarbonyl or alkylthiocarbonyl phosphine oxides and phosphonates with nitrogen nucleophiles (Equation (23)). The reaction proceeds smoothly with ammonia , primary amines , amino acids and diamines , and even with hydroxylamines , although in the latter case the reaction has to be carried out in pyridine to avoid formation of the Lossen rearrangement product. A variety of functional groups, such as alcohols, esters, or amides, is tolerated. EtO

O R EtO N P O OEt H

CH2Cl2, rt

OTMS

+

P OEt

RNCO

ð21Þ

R = Ph, 87% R = 4-O2NC6H4, 86%

Ph Ph O P C C N Ph Ph P Ph

+

Ph Ph P O

Toluene

PhNCO

NPh N Ph

Ph P Ph

reflux, 10 min

ð22Þ

O

75% 42

41

O

R3R4NH

R1 R2

P O

O R1 R2

X

NR3R4

P O

ð23Þ

X = OMe, SEt, OPh

P-Carbamoylation of 3-bis(siloxy)phosphinyl propanoate 43 under mild conditions with simultaneous elimination of TMSCl gave the functionalized carbamate 44 in 87% yield (Equation (24)) . O TMSO

ClCONMe2 P OTMS

OTMS

CH2Cl2 reflux

43

TMSO

O P

O

O OTMS NMe2

ð24Þ

44 87%

Studies on azide addition/Schmidt rearrangement of dialkyl acylphosphonates RCOPO(OR0 )2 revealed the formation of carbamoyl phosphonates RNHCOPO(OR0 )2 as the primary rearrangement products . However, the yields of these compounds depend on the substitution in the starting acyl phosphonate and usually do not exceed 20%, making this approach ineffective for the synthesis of carbamoyl phosphonates.

6.16.1.2.3

Carbonyl derivatives with one nitrogen and one arsenic function (carbamoyl arsines)

No information on the synthesis of tertiary carbamoyl arsines has been found in the literature. The data on secondary carbamoyl arsines are essentially limited to the single early article , already reviewed , which reported the preparation of these compounds via Sn-catalyzed addition of alkyl, cycloalkyl, and aryl arsines or their lithium derivatives to phenyl or cyclohexyl isocyanates.

471

Functions Containing a Carbonyl Group and Two Heteroatoms

The heterocycle 46, which could be considered as pyridine-fused cyclic carbamoyl arsine, existing, however, exclusively in the hydroxy form shown (Scheme 12), was prepared in a low yield by treatment of zwitterionic pyridooxadiazole 45 with tris(trimethylsilyl)arsine followed by hydrolysis .

i. (TMS)3As, MeCN 18% N N

+ O

N N

ii. MeOH, 2 h 82%

_

O

As OH

45

46

Scheme 12

6.16.1.2.4

Carbonyl derivatives with one nitrogen and one antimony function

No compounds of this type have been found in the literature.

6.16.1.2.5

Carbonyl derivatives with one nitrogen and one bismuth function

A single article, dealing with this class of compounds, reported the formation of quaternary carbamoyl bismuthanes on treatment of dimethylformamide-BiCl3 adduct with tertiary amines . To our knowledge, no more data on such compounds has appeared in the literature since.

6.16.1.3 6.16.1.3.1

Carbonyl Derivatives with One Nitrogen and One Metalloid (B, Si, Ge) Function Carbonyl derivatives with one nitrogen and one boron function

Carbamoyl boranes are generally prepared as adducts with tertiary amines, such as trialkyl amines, pyridine, or quinuclidine, via two synthetic approaches based either on amidation of amine-carboxyborane adducts or on hydrolysis of amine-cyanoboranes. Thus, direct coupling of trimethylamine-carboxyborane 47 with primary or secondary aliphatic or primary aromatic amines in the presence of the peptide-condensing agent dicyclohexylcarbodiimide (DCC) gave the corresponding carbamoylborane adducts 48 in moderate yields (Equation (25)) . A similar procedure was applied to the synthesis of the boron analog of hydroxamic acid using hydroxylamine hydrochloride in water instead of an amine . Me3N . BH2COOH

DCC +

R1R2NH

CH2Cl2

47

Me3N . BH2CONR1R2

ð25Þ

48

rt, 3 days 60–70%

The other general approach is based on a two-step procedure including addition of triethyloxonium tetrafluoroborate to cyanoborane adducts followed by basic hydrolysis of the intermediates 49 (Scheme 13).

A . BHRCN

– Et3O + BF 4

O +

– A . RHB C N Et BF4

49

Scheme 13

aq. NaOH 50–99%

A . RHB

NHEt

472

Functions Containing a Carbonyl Group and Two Heteroatoms

Both unsubstituted (R = H) and monosubstituted (R = Me, i-Pr, i-Bu, s-Bu, Bn) cyanoboranes could be used, whereas the second component (A) of the adduct could be a tertiary amine , triethyl phosphite , or phosphonate . The similar treatment of amine-dicyanoborane adduct afforded amine-bis(carbamoyl)boranes . Limitation of the above method to the preparation of ethylcarbamoyl boranes due to exclusive application of triethyloxonium tetrafluoroborate triggered a search for other synthetic procedures, which up to the early 2000s have been represented by single examples. Thus, addition of SbCl5 to Me3NBH2CN followed by treatment with t-butyl chloride and basic hydrolysis gives t-butylcarbamoyl borane adduct . Cyanation of diboratacyclohexane 50 with isonitrile 51 resulted in formation of the bridged salt product, which on hydrolysis with aq. NaOH gave N-unsubstituted carbamoyl boracycle 52 (Scheme 14) . H_ B I + N Me Me 50

i. CHCl3

Me + Me N _ H B H

+ _ Me3N.H2B–N C

+

ii. aq. NaOH

Me + Me N _ H B

80%

H

rt, 2 days

H_ NH2 B O N+ Me Me

52

51

Scheme 14

Reaction of pyridine-cyanoborane adduct 53 (R = CN) (Figure 2) with methyl triflate at 40
C in the absence of light gave the carbamoylborane adduct 53 (R = MeNHCO) in 19% yield . On stirring in methanol at room temperature (rt), the monomeric adduct of triphenylborane with 2-(trimethylsiloxy)phenyl isocyanide undergoes dimerization/rearrangement to afford heterocyclic diborane 54 in 20% yield . _H H + B N R

S S 53

Ph _ Ph H B N O + + N _O B Ph Ph

_ O Cp*Cl3 Ta

OH

N+

SiMe3

58

54

Figure 2 Examples of carbamoyl boranes and silanes.

6.16.1.3.2

Carbonyl derivatives with one nitrogen function and one silicon function (carbamoyl silanes)

Since the early report on the preparation of the first thermally stable carbamoyl silane Me3SiCONEt2 by silylation of dicarbamoyl mercury with hexamethyldisilathiane , several approaches to the construction of the NCOSi link have been developed, most of which, however, are applicable exclusively to tertiary carbamoyl silanes and suffer from severe limitations. Up to the early 2000s unstable secondary carbamoyl silanes have been prepared only by hydrosilylation of isocyanates either with t-BuPh2Li at 50
C or with Et3SiH in the presence of PdCl2 . Tertiary carbamoyl silanes 56, bearing a sterically hindered aryl group at the nitrogen atom, have been prepared, albeit in low yields, via carbonylation of lithiated silyl amides 55, generated in situ from the corresponding anilines and chlorosilanes, accompanied by 1,2-Si rearrangement (Scheme 15) . Ar

Li

N SiR3 55

i. CO (30 atm.) rt, 15 mi n ii. MeI, –78 °C 17–40%

R3 = Me3, PhMe2 Ar =2,6-R′2C6H3 (R′ = Me, Et, i-Pr)

Scheme 15

O Ar

SiR3 N Me 56

Functions Containing a Carbonyl Group and Two Heteroatoms

473

Silanes 56 could also be synthesized by sequential introduction of the carbonyl and trimethylsilyl group via carbonylation of mixed cuprates followed by silylation with a chlorosilane . Lithiation/silylation of formamide HCON(Me)CH2OMe afforded the corresponding carbamoyl silane Me3SiCON(Me)CH2OMe 57 in 61% yield . Although only the trimethylsilyl (TMS) group could be directly introduced by this procedure, a series of carbamoyl silanes were prepared via silyl group exchange by treatment of 57 with chlorosilanes at 145
C in the presence of CsF. Although the synthesis of carbamoyl silanes by silylation of carbamoyl chlorides seems obvious, the preparation of silanes (TMS)3SiC(O)NR2 (R = Me, Ph) from carbamoyl chlorides R2NCOCl and (TMS)3SiLi(THF)3 still represent the only example of such a transformation . Carbonylation of Cp*Cl3TaSiMe3 with limited quantities of CO followed by addition of pyridine or 2,6-dimethylpyridine gives the stable Ta-carbamoyl silane complex e.g., 58 (Figure 2), bearing a quaternary nitrogen atom .

6.16.1.3.3

Carbonyl derivatives with one nitrogen and one germanium function (carbamoyl germanes)

In contrast to the silicon analogs, only one example of synthesis of carbamoyl germanes using trialkylgermyl chloride has been reported up to the early 2000s . All the other known procedures use Et3GeLi as the germanium-introducing reagent. Thus, reaction of Et3GeLi with CF3C(O)NEt2 or Me3SiCCC(O)NMe2 under thermodynamic control conditions afforded carbamoyl germanes Et3GeC(O)NEt2 (56%) and Et3GeC(O)NMe2 (45%), respectively. The scope of the carbamoyl group-delivering reagents has been extended to carbamates (Equation (26)) . Me2NCOCl could also be used in this reaction as a carbamoylating reagent; however, in this case only 0.25 equiv. of the aluminum alkoxide should be employed due to its rate-inhibiting effect. O

O Et3GeLi

N

+

OMe

X

(sec-BuO)3Al (1 equiv.) Hexane / benzene 70–80 °C

6.16.1.4.1

GeEt3

ð26Þ

X = O, 54% X = CH2, 33%

3h

6.16.1.4

N X

Carbonyl Derivatives with One Nitrogen and One Metal Function Carbon monoxide insertion reactions

One of the most widely used methods for the preparation of carbamoyl metal complexes is based on the insertion of the carbon monoxide molecule into an already existing nitrogenmetal bond (Equation (27)). The examples of organometallic compounds involved in the transformation include: cuprates , complexes of nickel , iron , platinum , palladium , rhodium , iridium , ruthenium , rhenium , molybdenum , tungsten , thorium, and uranium . Molybdenum or copper complexes containing more than one metalnitrogen bond, such as Mo(NMe2)4 or lithium bis(amino)cuprates, undergo CO insertion into all these bonds even under mild reaction conditions. In contrast, carbonylation of tungsten complex W2Cl2(NMe2)4 with excess of CO in toluene/pyridine gave exclusively the monoinsertion product in 69% yield . O (L)n M NR2

CO

(L)n M

ð27Þ NR2

474

Functions Containing a Carbonyl Group and Two Heteroatoms

1,3-Dipolar cycloaddition reactions of (1,4-diaza-1,3-butadiene)tricarbonyliron complexes 59 (M = Fe) (Equation (28)) with electron-deficient alkynes, such as dimethyl acetylenedicarboxylate (DMAD) or methyl propiolate, in the presence of an external ligand L [L = CO, P(OMe)3] is accompanied by intramolecular insertion of a CO molecule into the metalnitrogen bond affording thermally labile bicyclo[2.2.1] adducts 60 in 60–95% yields . R N CO M CO N CO R

R2 R +

R1

R2

+

N

L O

N M R1OC

59

L CO

R

ð28Þ

60

M = Fe, Ru

R1 = R2 = CO2Me

R = i-Pr, t-Bu

R1 = H,

60–95%

R2 = CO

2Me

Analogous reactions of ruthenium complex 59 (M = Ru, R = i-Pr) with DMAD in the presence of CO or PPh3 as external ligands have been observed . In contrast to the iron analogs, which are unreactive toward electron-deficient alkenes, ruthenium complexes 59 (M = Ru; R = Me, i-Pr) undergo cycloaddition with dimethyl maleate or fumarate to afford the corresponding adducts in 70–90% yields .

6.16.1.4.2

Aminative carbonylation

Another widely used procedure for the preparation of carbamoyl metal compounds is based on the introduction of both carbonyl and amine moieties into the organometallic compound and is generally performed by carbonylation of a metal complex in the presence of a primary or a secondary amine. Although most commonly used in the synthesis of platinum and palladium carbamoyl compounds , this approach has also been applied to the preparation of carbamoyl stannanes , nickel , rhodium , ruthenium , and iron complexes. A modification of this procedure includes carbonylation of metal complexes in the presence of nitrobenzene as an amine precursor ; however, this reaction requires significantly higher temperatures (80–160
C) compared to the one using amines (0
C–rt). Indirect aminative carbonylation is represented by the reaction of Ph3PAuCl with methyl isocyanide in aq. KOH, which afforded the unstable carbamoyl gold complex Ph3PAuC(O)NHMe, presumably via hydrolysis of the intermediate isonitrile gold complex .

6.16.1.4.3

Amination

Currently, amination of metal carbonyl complexes represents the most common approach to the preparation of metal carbamoyl derivatives and has been successfully applied to the synthesis of carbamoyl complexes of Re , Mo , Ir , Os , Fe , Mn , Pd , Ru , Co , Cr , W , and Pt . Both neutral metal complexes (for Mo, Ir, Os, Pt, Mn, Ru, Fe) and cationic complexes (for Fe, Pd, Co, W, Pt, Re) could be used. The reactions can be accompanied by the loss of a nonreacting ligand . As nitrogen nucleophiles, both primary and secondary aliphatic amines , cyclic amines , aryl alkyl amines , anilines

Functions Containing a Carbonyl Group and Two Heteroatoms

475

, amino esters , hydrazines and even N-substituted aziridines (with aziridine ring opening) , and N-nitrosoamines were applied. An aromatic amine could also be generated in situ from the corresponding nitroarene under reductive conditions . In a metal complex with a ligand bearing a suitably located nucleophilic nitrogen atom, intramolecular amination can occur . The outcome of the reaction with diamines is determined by the starting organometallic compound: thus, cationic (OC)5ReFBF3 reacts with both amino groups of diaminoalkanes in a standard fashion affording the corresponding dicarbamoyl-bridged 2:1 complexes , whereas monoamination of (OC)5ReOSO2CF3 is followed by intramolecular attack of the second amino group at the central metal atom with formation of the cyclic carbamoylrhenium complex . Tetrakis(dimethylamino)methane, C(NMe2)4, has also been used as an efficient dimethylamino group donor for the preparation of Ru , Cr and W carbamoyl complexes under mild conditions. The reaction proceeds via insertion of one of the carbonyls of the metal carbonyl compound into the CN bond of the tetraaminomethane. A procedure based on a similar mechanism was applied for the preparation of a series of bimetallic complexes. Thus, reaction of carbonyl complexes M(CO)n (M = Fe, n = 5; M = Cr, Mo, W, n = 6) or Mn2(CO)10 with organometallic dimethylamides, such as Al(NMe2)3 , Ti(NMe2)4 , Zr(NMe2)4 or Cp*M0 (NMe2)3 (M0 = Ti, Zr) , gives the corresponding heterogeneous cluster compounds with M-CO-N fragment.

6.16.1.4.4

Reactions with heterocumulenes (isocyanates, ketenimines, azides, carbodiimides)

Reactions of neutral or cationic metal carbonyl complexes with isocyanates occur under mild conditions (neutral solvents, rt) and result in formation of the corresponding metallacyclic 1:1 adducts with a cycle size depending on the central metal and on the nature and reactivity of the ligands in the original complex. Thus, Cp2W(CO) gave four-membered metallacycles yielded six-membered metallacycle and Cp2V(CO) , whereas five-membered metallacycles 62 (X = S) were obtained from cationic Fe and Ru complexes 61 and isothiocyanates (Equation (29)) . Analogous reactions of the neutral complex (OC)2CpFePH(t-Bu) with isocyanates and isothiocyanates provided 62 [X = O, S; R1 = t-Bu, R2 = R3NHC( = X)] . Cp R1 OC M P R2 OC H 61

+ _

A

R3NCX

t-BuOK toluene, rt 68–83%

Cp R1 M P OC R2 O

X N 3 R 62 M = Fe, Ru; X = S; A = BF4, PF6;

ð29Þ

R1, R2 = i-Pr, t-Bu, Ph; R3 = Me, Et

This approach has also been applied to the preparation of cyclic carbamoyl mononuclear manganese , cobalt , iron and binuclear iron , iridium , and rhenium complexes. Potassium cyanate was utilized in the synthesis of five-membered carbamoyl platinacycle . 1,3-Cycloaddition of (5-MeC5H4)Mn(CO)2(THF) or Cp2Mo2(CO)4 with benzyl or aryl azides gave the corresponding binuclear adducts e.g., 63 (Figure 3) . Cluster Os3(CO)11(NCMe) reacted similarly , whereas reactions of cobalt and rhenium phosphine complexes CpM(CO)PR3 (M = Rh, R = i-Pr; M = Co, R = Me) occurred via azide degradation followed by [2+1] cycloaddition to give metallaaziridinones 64 (R0 = Ph, Ts) (Figure 3) in 69–79% yields . Metal carbonyl anions [CpFe(CO)2] and [Re(CO)5] undergo regiospecific [2+2] cycloaddition with ketenimines R1R2C¼C¼NR3 (R1 = R2 = Ph; R3 = Me, Ph) to give the isolable anionic complexes e.g., 65 (Figure 3) . Under similar conditions, the carbene iron complex (CO)4Fe¼C(OEt)Ph afforded acyclic -allyl,-complexes 66 (R1 = Me, Et, i-Pr; R2 = Me; R3 = Ph) .

476

Functions Containing a Carbonyl Group and Two Heteroatoms _

Me OC

Mn N

N N Ph

CO Mn CO O

Me

Ph

Cp R3P M N R′ 64

63

O

Ph

Ph

(OC)4 Re

N Ph O

R2

CO2Et

R1 (OC)3Fe

65

N R3 O

66

Figure 3 Carbamoyl metal complexes.

The reaction of Cp2W(CO) with diphenyl carbodiimide occurs by the same route as its reaction with isocyanates to give [2+2]-cycloaddition product, imino-substituted metallaazetidinone, in 94% yield . A similar formation of formal [2+2]-cycloaddition products was observed in the reactions of CpW(CO)3H and Cp*W(CO)3H with acyclic or cyclic sulfur diimides . The reactions are regioselective: in the case of monosubstituted sulfur diimides, only substituted nitrogen atom participates in the metallacycle construction. When sulfur diimides with electron-accepting substituents, such as Ts, were used, no cyclization was observed and only acyclic metalhydrogen bond insertion products were isolated.

6.16.1.4.5

Miscellaneous reactions

(i) Additions of metal carbonyls to iminophosphines and phosphine imides Treatment of Fe or Mo carbonyl complexes with iminophosphines results in ligation of the phosphorus to the metal atom followed by intramolecular attack of imine nitrogen at a CO ligand to afford the corresponding metallaphosphaazetidinones . In contrast, the analogous reactions with phosphine imides are accompanied with the cleavage of the phosphorusnitrogen bond giving metallapyrrolinone complexes in 69–72% yields .

(ii) Transmetallation Platinum and palladium carbamoyl complexes (Et2NCO)M(PPh3)2X (M = Pt, Pd, X = Cl; M = Pt, X = PPh3) were prepared in 75–87% yields by treatment of carbamoyl mercury compounds ClHgCONEt2 or Hg(CONEt2)2 with Pt(0) or Pd(0) triphenylphosphine complexes at 20
C in benzene .

(iii) Ligand modification reactions Treatment of transition metal complexes bearing an alkoxycarbonyl ligand with primary aliphatic or benzylic amines under mild conditions results in substitution of the alkoxy group with an alkylamino fragment. The reaction was applied to the preparation of Ru , Re and Fe carbamoyl complexes.

6.16.2

6.16.2.1

FUNCTIONS CONTAINING AT LEAST ONE PHOSPHORUS, ARSENIC, ANTIMONY, OR BISMUTH FUNCTION (AND NO HALOGEN, CHALCOGEN, OR NITROGEN FUNCTIONS) Carbonyl Derivatives with Two P, As, Sb, or Bi Functions

One of the few approaches to the preparation of carbonyl compounds with two phosphorus functions is based on the modification of the substituents on the central carbon of the already existing PCP fragment. Thus, the parent carbonylbis(phosphonic) diacid was prepared in

Functions Containing a Carbonyl Group and Two Heteroatoms

477

63% yield by basic hydrolysis of its dichloro derivative ; however, this procedure is restricted to this particular compound. Later, a series of carbonylbis(phosphonates) 68 (Equation (30)) was prepared by McKenna and co-workers by oxidation of the corresponding
-diazomethylenebis(phosphonate)s 67 with t-BuOCl. The product yields and formation of
,
-dichloro-substituted by-products depend on a solvent and the presence of water, with aq. EtOAc being preferred as a solvent . N2 O O P P OR RO OR OR 67

O O O P P OR RO OR OR

t-BuOCl aq. EtOAc 2–5 min 10–15 °C

ð30Þ

68 R = Me (93%), Et (94%) i-Pr (95%)

Another approach is based on the reaction of phosphines or their trimethylsilyl derivatives with phosgene. In this reaction, the secondary phosphines give acyclic carbonyldiphosphines , whereas primary phosphines and their silylated analogs afford four- or five-membered phosphacycles (Scheme 16) , presumably via dimerization of phosphaketene intermediates. O COCl2

Ph3CPH2

Et2O rt, 18 h 94%

R P

P R

COCl2 –60 °C

t-BuP(TMS)2

O R = t-Bu or Ph3C

Scheme 16

The formation of intermediate bis(phosphaketene) was also suggested for the preparation of anionic heterocycle 69 (Figure 4) by treatment of PCOLi with SO2 in dimethoxyethane (DME) at 50
C . Me2P Me2P –O

P

O

P P O

P 69

O–

Me2P

PMe2 P P O Th C C O P P Me2P

PMe2

PMe2

PMe2 70

Figure 4 Polycyclic phosphacarbonyl compounds.

Carbonylation of homoleptic eight-coordinated thorium dialkylphosphide Th[P(CH2CH2PMe2)2]4 in hydrocarbons afforded the double insertion product 70 (Figure 4) in 73% yield . The similar carbonyl bridge formation between phosphorus ligands was observed in reactions of sterically hindered (dialkylamino)dichlorophosphines with tetracarbonyl ferrate as the carbon monoxide source . The mechanism of this transformation, steric requirements, and substituent effects have been studied in detail . Organometallic compounds bearing a PCOP unit were also prepared via carbonylative PP bond cleavage of metal diphosphine complexes. Thus, cleavage of the PP bond with insertion of carbon monoxide was observed on treatment of iron complexes 71 or 72 with CO or excess Fe2(CO)9 (Scheme 17) or by ring opening–ring closure of substituted cyclotetraphosphane in the presence of Fe2(CO)9 .

478

Functions Containing a Carbonyl Group and Two Heteroatoms O But

But

P P (OC)3Fe Fe(CO)3 71

CO

t R P P Bu (OC)3Fe Fe(CO)3

Benzene 80 °C, 20 h

73

75%

Fe2(CO)9 THF rt, 2 days

But P P (OC)3Fe Fe(CO)3 R

72

44%

R = t-Bu, Cp*Fe(CO)2

R = Cp*Fe(CO)2

Scheme 17

Cleavage of the phosphorusphosphorus double bond followed by carbon monoxide insertion on treatment of a series of Fe, Ru, or Os diphosphene complexes with excess of Fe2(CO)9 in toluene affords the corresponding metallated diphosphinomethanone complexes, analogs of 73 . No information on the synthesis of carbonyl derivatives with two As, Sb, or Bi functions, or unsymmetrical analogs has been found up to the early 2000s.

6.16.2.2

Carbonyl Derivatives with One Phosphorus and One Metal Function

The most important approaches to the preparation of carbonyl compounds with one phosphorus and one metal function are based on: (a) carbon monoxide insertion into the metalphosphorus bond; (b) formation of PCO bond via phosphinylation of metal carbonyls; (c) formation of the MCO bond via reaction of metal complexes with
-keto phosphonates; and (d) carbonylative phosphinylation of metal complexes. The carbonylation approach has been successfully applied to the preparation of hafnium , thorium 70 (Figure 4) , and zirconium complexes under mild conditions. A series of phosphinocarbonyl complexes 75 was synthesized by reaction of cationic complexes 74 with the corresponding lithium phosphides (Equation (31)) . The polarity of the reagent can also be reversed: thus, anionic bimetallic complex (CpLi+)(CO)3MoCo(CO)4 readily reacted with chlorodiphenyl phosphine to give Mo2Co product with a carbonyl bridge between phosphorus and cobalt atoms .

–78 to 0 °C

_

[Cp*M(CO)3]+BF4

+

LiPR1R2

Et2O 30 min

74

O OC R1 P M OC Cp* R2

ð31Þ

75 M = Fe, Ru R1, R2 = TMS, t-Bu

Neutral phosphines and phosphites were also applied for phosphinylation of carbonyl complexes of molybdenum , iridium , and tantalum . Reaction of Ni(COD)2 with
-keto phosphonates in the presence of PPh3 affords 2-CO coordinated complexes 76 (Equation (32)) . O Ni(COD)2 +

R

P O

OMe OMe

PPh3 Et2O rt

Ph3P O Ni OMe P R Ph3P OMe O 76

R = Me (79%), Et (89%), Ph (73%), 4-ClC6H4 (65%), 4-MeC6H4 (72%)

ð32Þ

479

Functions Containing a Carbonyl Group and Two Heteroatoms

Treatment of Cp*Cl3TaSiMe3 with trialkyl phosphines or phosphites under CO atmosphere results in carbonylative phosphinylation of the tantalum complex to give adducts 77 (Figure 5) , whereas carbonylation of zirconocenes bearing a phosphinefunctionalized cyclopentadiene ring affords intramolecular phosphinylation products 78 . Cp* _ O Cp*Cl3 Ta C

R3P +

R2 Zr

SiMe3

C

R = Me, Et, OMe

Ru

R1 – O

Ru C

Me

R1

92

78 1

R2

Cp*

PPh 2 +

77

C

OC

2

1

R = Me, Et; R2 = H, Me

R = Cl, Me; R = H, PPh2

Figure 5 Examples of carbonyl compounds with one phosphorus and one metal or two metal functions.

6.16.2.3

Carbonyl Derivatives with One B, As, Sb, or Bi Function, and One Metal Function

The reaction of 9-o- or 9-m-carboranecarbonyl chlorides with NaRe(CO)5 in THF at 70
C gave the corresponding Re-complexes C2H2B10-CORe(CO)5 in 58–67% yields . The transmetallation of solvated lithium complex of arsadionate 79 using RuCl2(PPh3)3 in DME afforded the Ru complex 80 with not fully delocalized arsadionate ligand (Equation (33)) . In contrast, the analogous reactions with FeCl2 or CoCl2 gave the complexes with planar arsadionate ligands, coordinated to the metal center in a chelating 2-O,O-fashion. But

But

RuCl2(PPh3)3

O Li Li O O

DME, –78 °C

As O

But

As

But O

O Ru

Cl

73%

But

As

But

ð33Þ

PPh3 PPh3 80

79

No data on the preparation of carbonyl compounds with one Sb or Bi, and one metal function have been reported up to the early 2000s.

6.16.3

6.16.3.1

FUNCTIONS CONTAINING AT LEAST ONE METALLOID FUNCTION (AND NO HALOGEN, CHALCOGEN, OR GROUP 5 ELEMENT FUNCTIONS) Carbonyl Derivatives with Two Silicon Functions

Two major approaches to the preparation of symmetrical bis(silyl) ketones involve C¼O bond formation in the pre-existing SiCSi fragment and are based on oxidation and hydrolysis reactions. Since the early synthesis of bis(triphenylsilyl) ketone via oxidation of the corresponding alcohol , the efforts were concentrated mostly on the preparation of the simplest representative of this class, bis(trimethylsilyl) ketone. In the oxidative approach, (Me3Si)2CO 83 (Scheme 18) was readily prepared via ozonation of bis(silylated) ylide 81 or by oxidation of trimethylsilyl derivative 82 with m-chloroperbenzoic acid (MCPBA) . O3 . P(OPh)3

TMS C PPh3 TMS 81

–78 °C Toluene 30–50%

TMS O TMS 83

Scheme 18

MCPBA –78 °C CH2Cl2 45%

TMS TMS

SMe TMS 82

480

Functions Containing a Carbonyl Group and Two Heteroatoms

In the hydrolytic approach, preferred due to oxidizability of 83,
-halo ethers 85, prepared by cleavage of O,S-acetal 84 with Br2 or SO2Cl2, readily hydrolyze on passing through a silica gel or alumina column to afford TMS2CO in 65–75% yields (Scheme 19) .

TMS

TMS PhS

Br2 or SO2Cl2

TMS X

CH2Cl2

OMe

TMS OMe 85

84

Silica gel pentane ether

TMS

75–78%

83

O TMS

X = Cl (65%) X = Br (82%)

Scheme 19

Similarly, bis(silyl)bis(methylthio) ketone 86, obtained by double lithiation/silylation of bis(methylthio)methane, undergoes hydrolysis on treatment with HgOBF3  Et2O to give bis(dimethylphenylsilyl) ketone (Equation (34)) . MeS

HgO-BF3.Et2O

SMe

PhMe2Si

56%

SiMe2Ph

O PhMe2Si

ð34Þ

SiMe2Ph

86

To our knowledge, no isolable unsymmetrical bis(silyl)ketones have been synthesized up to the early 2000s, although the formation of (trimethylsilyl)(triphenylsilyl) ketone on hydrolysis of the corresponding 2,2-disilylated 1,3-dithiane was proposed on the basis of infrared spectra .

6.16.3.2

Other Carbonyl Derivatives with Two Metalloid Functions

The first bis(germyl) ketone, Et3GeCOGeEt3, was prepared via neutral hydrolysis of the corresponding 2,2-digermyl 1,3-dithiane derivative and characterized in solution . One year later, bis(triphenylgermyl) ketone was prepared in 73% yield by oxidation of the corresponding alcohol and fully characterized . Since then, only one procedure for the preparation of these compounds has been reported: bis(trimethylgermyl) ketone 89 (M = Ge) was synthesized via germylation of thioacetal 87 followed by halogenation of 88 with SO2Cl2 and mild hydrolysis of the intermediate
-chloro ether on silica gel (Scheme 20) . Mixed (trimethylsilyl)(trimethylgermyl) ketone 89 (M = Si) was prepared similarly (Scheme 20). No data on synthesis of other carbonyl compounds with two metalloid functions have been found up to the early 2000s.

GeMe3

i. t-BuLi, THF –78 °C

OMe ii. Me 3MX

PhS 87

Me3M PhS

GeMe3 OMe

i. SO 2Cl2, CH2Cl2 0 °C, 30 min

ii. Cyclohexene THF, –78 °C 0 °C, 30 min 88 M = Si, X = Cl, 90% iii. Silica gel M = Ge, X = Br, 92% pentane

O Me3M

GeMe3 89

M = Si, 53% M = Ge, 65%

Scheme 20

6.16.3.3

Carbonyl Derivatives with One Metalloid and One Metal Function

The most general approach to the preparation of the silaacyl metal compounds is based in the insertion of carbon monoxide into the metalsilicon bond. Thus, carbonylation of silyl zirconium complexes 90 gives 2-silaacyl complexes 91 (Equation (35)) .

Functions Containing a Carbonyl Group and Two Heteroatoms R2 R1

Cp Zr SiR33 90

CO (100 psi) rt pentane or Et2O 71–90%

R2 R1

Cp Zr

481

SiR33

O 91

ð35Þ

R1 = Cp, Cp*; R2 = Cl, TMS R3 = Me, TMS

Analogous products, prepared from complexes bearing disubstituted silyl moiety, have been found to be unstable . A similar procedure was applied for the preparation of 2-silaacyl complexes of Re , Ta , and Fe . In the latter case Fe2(CO)9 was used as a carbon monoxide source. No information on the synthesis of other carbonyl compounds with one metalloid and one metal function has been found up to the early 2000s.

6.16.4

CARBONYL DERIVATIVES CONTAINING TWO METAL FUNCTIONS

Detailed information on both homonuclear and heteronuclear polymetallic clusters with a CO bridging ligand can be found in the appropriate volumes of Comprehensive Organometallic Chemistry-II and in a series of yearly reviews titled ‘‘Organo-Transition Metal Cluster Compounds’’, published in Organometallic Chemistry e.g., , so the following survey is intended to give only a brief summary of the methods used for the preparation of title compounds in the period 1994–2003. One of the most widely used approaches for the preparation of homonuclear bimetallic clusters with a CO bridging ligand is based on reductive carbonylation of the corresponding metal halides in ethylene glycol , or on the surface of inorganic oxides or zeolites , or carbonylation of neutral metal complexes . Enals, such as crotonaldehyde or 2-pentenal, could serve as a source of bridging CO: thus, treatment of [Cp*RuCl]4 with these enals in the presence of K2CO3 gave diruthenium complexes 92 (Figure 5) in 36–65% yields . Other dirhodium and dirhenium clusters were obtained by dimerization of the corresponding monomeric rhodium and rhenium carbonyls at room temperature or on heating . Dimerization of indenyl rhenium tricarbonyl under UV irradiation was accompanied by loss of one CO ligand . Another approach, applied to the preparation of both homonuclear and heteronuclear bimetallic CO-bridged complexes, includes reaction of metalmetal bonded carbonyl compounds with external ligands, such as PPh3 , acetonitrile , or alkynes , which force one of CO ligands to change its binding mode. Similarly, the reaction of iron carbonyls with t-BuGeH3 or Cp*2GaCl yielded ironiron bonded complexes containing both -germylene or -gallium and -CO bridges. A similar procedure was applied to the preparation of heteronuclear clusters, such as CObridged RuPd , IrMo, IrW, IrFe , FeRe, and FeMn complexes .

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487

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492 2002MI673 2002MI785 2002MI963 2002OL597 2002OL4033 2002OL4639 2002OL4673 2002OM3108 2002OM4847 2002PS(177)1303 2002SC803 2002SC2613 2002SC3373 2002SL1779 2002T4225 2002T7207 2002TL4313 2002TL6431 2002TL6649 2002WOP66442 2002WOP83642 2002ZN(B)937 2003CC486 2003CRV3707 2003JCO155 2003JCO632 2003JMC113 2003JMC1112 2003JMC3758 2003JMOC(A)135 2003JOC754 2003JOC1615 2003JOC1626 2003JOC5512 2003JOM(669)44 2003MI425 2003OL2555 2003PS(178)61 2003SC1449 2003T1731 2003TL591 2003TL811 2003TL2065

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Biographical sketch

Olga Denisko was born in Krasnoyarsk, Russia and studied at Moscow State University, Russia, where she obtained her Ph.D. in 1993 under the direction of Professor N. S. Zefirov. During 1994–1996, she worked as a Postdoctoral Research Fellow in the Center for Heterocyclic Compounds, University of Florida, FL under supervision of Professor A. R. Katritzky, after which she returned to Russia and was employed as a Chemist in the Central Laboratory of ‘‘Krasfarma’’ Pharmaceuticals (Krasnoyarsk, Russia). In 1998, she returned to the University of Florida as Postdoctoral Research Fellow/Group Leader. After working there for another two years, she was employed as a Senior Research Chemist by Alchem Laboratories (Alachua, FL). In June 2002, she took up her present position as Assistant Scientific Information Analyst at the Chemical Abstracts Service, Columbus, OH. Her scientific research interests include various aspects of heterocyclic organic chemistry and chemistry of organosulfur compounds.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 453–493

6.17 Functions Containing a Thiocarbonyl Group and at Least One Halogen; Also at Least One Chalcogen and No Halogen E. KLEINPETER University of Potsdam, Potsdam, Germany 6.17.1 FUNCTIONS CONTAINING AT LEAST ONE HALOGEN 6.17.1.1 Thiocarbonyl Halides Containing Two Halogens 6.17.1.2 Sulfoxides of Thiocarbonyl Halides (Sulfines) 6.17.1.3 Thiocarbonyl Halides Containing One Halogen and One Other Heteroatom 6.17.1.3.1 Halogenothioformates, ROC(Hal)¼S 6.17.1.3.2 Chlorothioformates, ROC(Cl)¼S 6.17.1.3.3 Halogenodithioformates, RSC(Hal)¼S 6.17.1.3.4 Chlorodithioformates, RSC(Cl)¼S 6.17.1.3.5 Thiocarbamoyl halides, R2NC(Hal)¼S 6.17.1.3.6 Thiocarbamoyl chlorides, R2NC(Cl)¼S 6.17.2 FUNCTIONS CONTAINING AT LEAST ONE CHALCOGEN FUNCTION (AND NO HALOGEN) 6.17.2.1 Thionocarbonates (O,O-Diesters of Thiocarbonic Acid) 6.17.2.1.1 From thiophosgene 6.17.2.1.2 From chlorothionoformates 6.17.2.1.3 From thiocarbonyldiimidazole 6.17.2.2 Dithiocarbonates (Esters of Dithiocarbonic Acid) 6.17.2.2.1 Salts of O-alkyl esters of dithiocarbonic acid (xanthates) and bisalkoxythiocarbonyl disulfides 6.17.2.2.2 O,S-Diesters of dithiocarbonic acid 6.17.2.2.3 Sulfoxides of O,S-diesters of dithiocarbonic acid (sulfines) 6.17.2.3 Thiocarbamates (Esters of Thiocarbamic Acid) 6.17.2.3.1 From O-alkyl or O-aryl chloroformates and amines 6.17.2.3.2 From N,N-dialkylthiocarbamoylchlorides and alcohols or phenols 6.17.2.3.3 From N,N 0 -thiocarbonyl diimidazole and alcohols 6.17.2.3.4 From thiophosgene and 1,2-amino alcohols 6.17.2.3.5 From CS2 and 1,2-amino alcohols 6.17.2.3.6 From isothiocyanates and alcohols 6.17.2.3.7 N-acyl-1,3-oxazolidine-2-thiones as auxiliary agents 6.17.2.3.8 By thermal conversion of 2-allyl thiobenzothiazoles 6.17.2.3.9 Other methods 6.17.2.4 Dithiocarbamates (Esters of Dithiocarbamic Acid) 6.17.2.4.1 Alkali metal salts of N,N 0 -disubstituted dithiocarbamic acid (dithiocarbamates)

495

495 495 497 498 498 498 499 500 501 501 502 502 503 504 509 510 510 511 519 520 520 521 521 521 522 523 528 528 528 530 530

496

Functions Containing a Thiocarbonyl Group and at Least One Halogen 530 534 534 534 534

6.17.2.4.2 Esters of dithiocarbamic acids 6.17.2.4.3 Bis-[thiocarbamoyl](thiuram)disulfides 6.17.2.5 Trithiocarbonates (Esters of Trithiocarbonic Acid) 6.17.2.5.1 Salts of monoesters of trithiocarbonic acid 6.17.2.5.2 Diesters of trithiocarbonic acid

6.17.1 6.17.1.1

FUNCTIONS CONTAINING AT LEAST ONE HALOGEN Thiocarbonyl Halides Containing Two Halogens

All four thiocarbonyl halides with identical halogens are known and were synthesized prior to 1995 (see Table 1 for characteristic properties). Thiocarbonyl diiodide is the only one that has not been isolated, due to its labile nature, thus far and its identification has been based on IR. These compounds tend to polymerize easily and their stability is dependent on both the character of the C¼S double bond and the donor activity of the attendant halogens . As acid halides, they react readily with alcohols, amines, etc., to yield the corresponding carbonic acid derivatives in high yields. Some thiocarbonyl halides with dissimilar halogens have also been synthesized and are included in Table 1. Caution! Thiocarbonyl halides must be handled with great care as they are highly toxic and it is imperative that exposure by ingestion, inhalation, or direct absorption through the skin be avoided. As a minimum precaution, all operations should be conducted in a well-ventilated fume hood. Table 1

Thiocarbonyl halides—properties and references for the most useful syntheses

Compound F2C¼S Cl2C¼S Br2C¼S I2C¼S FClC¼S FBrC¼S ClBrC¼S

Properties

References

Colorless gas, b.p. 54
C Red liquid, b.p. 73.5
C Orange-red liquid, b.p. 142–144
C Not yet isolated; identification by IR,
C¼S = 1062 cm1 and
CI = 602 cm1 Yellow liquid, b.p. 7
C Yellow liquid, b.p. 4–8
C (100 mmHg) Red liquid, b.p. 47
C (80 mmHg)



The syntheses of the thiocarbonyl halides have been extensively reviewed in COFGT (1995), and the references for the most useful syntheses are collected in Table 1. The most convenient synthesis of thiophosgene (Cl2C¼S) is by the reduction of perchloromethylsulfenylchloride (Cl3CSCl) with H2S at 110–114
C ; other reducing agents have also been used. Alternatively, trichloromethyl thiol (Cl3CSH) can be reduced with SO2 in the presence of KI and S2Cl2 to provide thiophosgene (Scheme 1).

Cl3C SCl

Cl3C SCl

Reduction H2S, 114 °C 96%

Reduction (SO2, KI, S2Cl2) 97%

Cl S C Cl

Cl S C Cl

Scheme 1

The other three symmetric thiocarbonyl halides are, in fact, available by the direct derivatization of thiophosgene. However, the most useful syntheses are as follows: F2C¼S by a three-step procedure via dimerized thiophosgene which is fluorinated using SbF3 and the resulting 2,2,4,4tetrafluoro-1,3-dithietane decomposed by pyrolysis (Scheme 2).

497

Functions Containing a Thiocarbonyl Group and at Least One Halogen Cl

Cl

S

Cl

Cl

Cl

S

F

SbF3

2S C Cl

F

S S

F

(475 –500 °C)

F 2S C

90%

F

F

Scheme 2

Br2C¼S from F2C¼S in 97% yield by reaction with anhydrous HBr and I2C¼S from carbon monosulfide by reaction with I2 . The three thiocarbonyl halides with dissimilar halogens reported thus far have been obtained as follows: FClC¼S from FCl2CSCl in 87% yield by reduction using Sn/HClconc ; FBrC¼S from FClC¼S by halogen exchange using BBr3 at 65
C and ClBrC¼S from thiophosgene by halogen exchange using BBr3 . The high-temperature thiation of thiophosgene with elemental sulfur has been reinvestigated by Christensen and Senning . The reaction was shown to lead to a multitude of primary, secondary, and tertiary products which are probably the result of the cycloaddition of thiophosgene S-sulfide Cl2C¼S¼S and/or thiophosgene S-disulfide Cl2C¼S¼S¼S followed by sulfur extrusion and various dechlorination/chlorination steps.

6.17.1.2

Sulfoxides of Thiocarbonyl Halides (Sulfines)

Four sulfoxides of thiocarbonyl halides are known thus far and all were synthesized prior to 1995 (see Table 2 for characteristic properties and the most useful syntheses). They are very labile compounds and can be detected only under extreme conditions except for thiophosgene-S-oxide (dichlorosulfine). The synthesis, structural analysis, and chemistry of dichlorosulfine have been reviewed . In its simplest preparation, it is obtained from 2,2,4,4-tetrachloro-1, 3-dithietane by oxidation using trifluoroperoxyacetic acid at 40
C and the resulting 1,3-dioxide quantitatively cleaved by vacuum pyrolysis at 480
C and 0.5 mmHg (Scheme 3).

Table 2 Sulfoxides of thiocarbonyl halides—properties and references for the most useful syntheses Compound

Properties

References




Decomposes at 100 C; detected by MS Yellow liquid, b.p. 34–36
C (25 mmHg) Reddish liquid; identified by IR in an argon matrix Decomposes at 100
C; detected by MS

F2C¼SO Cl2C¼SO Br2C¼SO FClC¼SO

Cl Cl

S S

Cl Cl

CF3CO3H, CH2Cl2

Cl

40 °C

Cl

O S S O

Cl Cl

∆ 51%



Cl O S C Cl

Scheme 3

Dichlorosulfine can also be obtained from thiophosgene directly (by oxidation using peroxybenzoic acid ), from Cl3CSCl (by hydrolysis ) and from allyl trichloromethyl sulfoxide Cl3CSOCH2CH¼CH2 (by pyrolysis at 300–400
C ). It is much more difficult to synthesize than the other three sulfoxides reported thus far (all were obtained prior to 1995), since they decompose spontaneously at low temperatures. None have been isolated, but some have been identified on the basis of IR and MS analyses (cf. COFGT (1995)).

498

Functions Containing a Thiocarbonyl Group and at Least One Halogen

6.17.1.3

Thiocarbonyl Halides Containing One Halogen and One Other Heteroatom

6.17.1.3.1

Halogenothioformates, ROC(Hal)¼S

The syntheses of both fluoro- and chlorothioformates have been reported. Thiocarbonyl chloride fluoride (ClFC¼S) reacts readily with alcohols in the absence of solvent leading selectively to the alkyl fluorothioformates ROC(F)¼S (R = alkyl) . In particular, the aryl chlorothioformates (PhOC(Cl)¼S) have been employed extensively as starting reagents for the syntheses of the corresponding di- and trithiocarbonates and thiocarbamates (vide infra). The syntheses of bromo- and iodothioformates have not been reported as of early 2004.

6.17.1.3.2

Chlorothioformates, ROC(Cl)¼S

Phenols and its analogs react readily with thiophosgene in (chloro)hydrocarbon solvents together with base to provide the corresponding aryl chlorothioformates in excellent yields, e.g., (Equation (1)). Cl

Cl

Cl Cl

Cl

OH

+

S C Cl

Cl

NaOH –HCl 99%

Cl

Cl Cl S

Cl

O

ð1Þ Cl

Cl

Colorless solid; m.p. 108–112 °C

Phenyl chlorothioformate PhOC(Cl)¼S, a yellow liquid boiling at 91
C (10 mmHg), can be synthesized easily employing this procedure with yields in excess of 95% (cf. COFGT (1995), ). This compound has often been used for the syntheses of the corresponding di- and trithiocarbonates and thiocarbamates (vide infra) and has proven to be very useful for introducing the thiocarbonyl functionality into organic compounds (vide infra). The in situ preparation of thiophosgene for the generation of phenyl chlorothioformate has been accomplished by the chlorination of CS2, by the reduction of CCl3CSCl, or by the reduction of CCl3SH using SO2 (COFGT (1995)). The corresponding alkyl chlorothioformates (e.g., ethyl chlorothioformate, a yellow liquid, b.p. 53–55
C (40 mmHg)) can be synthesized by three different approaches. (i) From thiophosgene, by the reaction with potassium alkoxide in the corresponding alcohol at low temperatures; yields are in excess of 90%, cf. Table 3 . (ii) From thiophosgene, by the reaction with alkoxytrimethylsilanes; although not requiring basic conditions, the yields, however, are less than 35% . (iii) By the chlorination of bis(alkoxythiocarbonyl)disulfides with Cl2 or SOCl2 . However, the yields are low, under 70%, and the reaction products are difficult to purify. In addition, it is strongly advised that only very pure reagents be used for the preparation (Scheme 4). Table 3

Chlorothioformates—properties and yields Yield (%)

Compound EtOC(Cl)¼S n-BuOC(Cl)¼S

81 85

n-PrOC(Cl)¼S i-PrOC(Cl)¼S i-BuOC(Cl)¼S

91 88b 89

a

.

b

Properties b.p. 46
C (33 mmHg); n18 D 1.4879,
C¼S b.p. 62
C (12 mmHg); n18 D 1.4815,
C¼S spectroscopic data provideda b.p. 42
C (12 mmHg); n18 D 1.4885,
C¼S b.p. 34
C (10 mmHg);
C¼S 1280 cm1 b.p. 54
C (10 mmHg); n18 D 1.4776,
C¼S

1270 cm1 1260 cm1; 1260 cm1 1278 cm1

In THF.

In the development of non-nucleoside reverse transcriptase inhibitors and as part of a total synthesis of such, Hahn and co-workers synthesized i-propyl chlorothioformate (i-PrOC(Cl)¼S) from i-propanol and thiophosgene (in DMF/Et3N). The i-propyl chlorothioformate

499

Functions Containing a Thiocarbonyl Group and at Least One Halogen

(i) AlkOK

+

Cl

AlkOH –65 °C

S C Cl

(ii) AlkO SiMe3

S C Cl

(iii) AlkO C

S S C OAlk

C S AlkO

Cl

Cl +

Cl

80 °C

Cl2 or SOCl 2

C S AlkO

Cl C S AlkO

S S

Scheme 4

was not isolated but treated with a number of substituted anilines to provide the corresponding thiocarbamates (i-PrOC(S)NHAryl) in low yield .

6.17.1.3.3

Halogenodithioformates, RSC(Hal)¼S

A number of halogenodithioformates RSC(Hal)¼S have been prepared, and are presented together with their most useful syntheses in Table 4. The most effective route for the synthesis of F3CC(F)¼S is by the reaction of FClC¼S with Hg(SCF3)2 at room temperature (yield, 96%). In a similar fashion, C6F5SC(Cl)¼S was obtained from Hg(SC6F5)2 and thiophosgene and F3CSeC(F)¼S from Hg(SeCF3)2 and FClC¼S at 78
C . A few halogenodithioformates have also been obtained by the reaction between thiols (RSH) and the corresponding thiocarbonyldihalogenides (Hal2C¼S) (COFGT (1995)): AlkSC(F)¼S in the absence of solvent ; AlkSC(Cl)¼S in dry CS2 at room temperature in 55–70% yield ; and AlkSC(Br)¼S in ether at room temperature under argon . Table 4 Halogenodithioformates—properties and references for the most useful syntheses Compound

Properties

CF3SC(F)¼S CF3SC(Cl)¼S CCl3SC(Cl)¼S C2Cl5SC(Cl)¼S EtSC(Br)¼S




n-PrSC(Br)¼S n-PrSC(Cl)¼S i-PrSC(Cl)¼S n-BuSC(Cl)¼S CF3SC(Br)¼S CF3SeC(F)¼S CF3SeC(Cl)¼S CF3SeC(Br)¼S EtSeC(Cl)¼S i-PrSeC(Cl)¼S CF3SeC(Cl)¼SO CF3SeC(Br)¼SO

Yellow liquid, b.p. 43 C Orange oil, b.p. 98–100
C (14 mmHg) Orange oil, b.p. 78–80
C (0.04 mmHg) Orange oil, b.p. 108–109
C (0.03 mmHg) Deep red liquid, storage at 20
C under argon required; spectroscopic data provided Deep red liquid, storage at 20
C under argon required; spectroscopic data provided Yellow liquid, b.p. 57
C (21 mmHg); nrtD 1.5795, spectroscopic data provided Yellow liquid, b.p. 83–85
C (21 mmHg); nrtD 1.5699, spectroscopic data provided Yellow liquid, b.p. 103–104
C (21 mmHg); nrtD 1.5696, spectroscopic data provided Red liquid, b.p. 57–58
C; spectroscopic data provided b.p. 57–58
C; spectroscopic data provided Yellow viscous oil Liquid, b.p. 54
C (50 mmHg); spectroscopic data provided Red, viscous oil, b.p. 88
C (23 mmHg); spectroscopic data provided Red, viscous oil, b.p. 102–104
C (23 mmHg); spectroscopic data provided Yellow liquid, b.p. 47
C (10 mmHg) Yellow liquid, b.p. 60
C (10 mmHg)

References

500

Functions Containing a Thiocarbonyl Group and at Least One Halogen

The analogous selenoesters (AlkSeC(Cl)¼S) have also been produced from the reaction of alkyl selenols . In addition, F3CSeC(Cl)¼S has been synthesized from F3CSeC(F)¼S in 97% yield by halogen exchange using BCl3 and F3CSeC(Br)¼S from F3CSeC(F)¼S after UV irradiation for 4 h and halogen exchange with BBr3 at 40
C in 74% yield . The sulfines were produced by oxidation of the halogenodithioformates using m-chloroperoxybenzoic acid (MCPBA) .

6.17.1.3.4

Chlorodithioformates, RSC(Cl)¼S

There are five main routes available for the synthesis of the chlorodithioformates.

(i) From thiols For example, alkyl chlorodithioformates (cf. Table 4) can be easily synthesized from the corresponding alkyl thiols and thiophosgene in good yields at room temperature , and similarly from the aryl thiols .

(ii) By the insertion of carbon monosulfide This method has been employed for the syntheses of a number of alkyl and aryl chlorodithioformates . (It should be noted that the continuous production of CS requires special care and equipment .)

(iii) From sulfochlorides For example, methyl chlorodithioformate MeSC(Cl)¼S can be obtained from (MeS)2CClSCl by hydrolysis (using water, aqueous KI, or MeSH), from MeSC(Cl)2SSMe (again by hydrolysis using water, aqueous KI, or MeSH), or from MeSC(Cl)2SCl (using MeSH) .

(iv) From alkali metal dichlorodithioformates Alkali metal dichlorodithioformates MSC(Cl)¼S, prepared from alkali chlorides/NaOH and CS2 , have been alkylated, for example, using ethyl iodide to yield ethyl chlorodithioformate EtOC(Cl)¼S .

(v) From arenediazonium salts and CS2 Aryl chlorodithioformates have been produced by the reaction of arene diazonium chlorides with CS2 under Sandmeyer conditions (Cupowder or CuCl at room temperature) (Scheme 5). Cl +

(i)

C S

CS2 CuCl

–

N N Cl

S

X

X Cl Cl

(ii)

SH + S C X

Cl

C S

NaOH, CHCl3

S

–HCl

Scheme 5

X

501

Functions Containing a Thiocarbonyl Group and at Least One Halogen 6.17.1.3.5

Thiocarbamoyl halides, R2NC(Hal)¼S

In addition to a number of thiocarbamoyl chlorides (R2NC(Cl)¼S), some fluoride and bromide analogs have also been synthesized. Only the N,N-disubstituted derivatives of thiocarbamoyl halides are sufficiently stable to enable isolation; the N-monosubstituted thiocarbamoyl halides decompose spontaneously after formation to the corresponding isothiocyanates with the evolution of HCl. Fluorothiocarbamates have been obtained directly from the reaction between thiocarbonyl chloride fluoride and secondary amines. A few other patented methods have been reported, e.g., N,N-dimethylthiocarbamoyl fluoride was obtained by treating F2C¼CFR (R = H, Cl, CF3) with tetramethylthiouramide sulfide at 130–135
C (COFGT (1995)). The thiocarbamoyl bromides R2NC(Br)¼S known thus far have been produced by the reaction between bromine and the thiocarbamoyl chlorides R2NC(Cl)¼S.

6.17.1.3.6

Thiocarbamoyl chlorides, R2NC(Cl)¼S

Thiocarbamoyl chlorides are sufficiently stable to permit isolation; selected examples are listed in Table 5. Dimethyl and diethylthiocarbamoyl chloride and other N,N-disubstituted analogs continue to be very popular as reagents for introducing sulfur into organic compounds. Dimethylthiocarbamoyl chloride has been investigated using gas-phase electron diffraction ; the molecule exists as a single near-planar conformer in the gas phase.

Table 5

Thiocarbamoyl chlorides—properties and references for the most useful syntheses

Compound Me2NC(Cl)¼S Et2NC(Cl)¼S Et2NC(Cl)¼S O(CH2CH2)2NC(Cl)¼S Ar,a MeNC(Cl)¼S Ar,b MeNC(Cl)¼S Ar,c MeNC(Cl)¼S Me2NN(Me)C(Cl)¼S Me2NN(R)C(Cl)¼Sd R2NN(Me)C(Cl)¼Se R2NN(Me)C(Cl)¼Sf a d

Properties; method; yield

References

m.p. 43 C; chlorination using SO2Cl2; 97% b.p. 100
C (21 mmHg); Me2NH, S¼CCl2; 46% b.p. 70
C (13 mmHg); chlorination using SO2Cl2; 97% b.p. 96
C (17 mmHg); O(CH2CH2)2NH, S¼CCl2; 83% m.p. 44–45
C; chlorination using CSCl2; 45% m.p. 79–80
C; chlorination using CSCl2; 80% m.p. 108–109
C; chlorination using CSCl2; 80% m.p. 64–65
C; method (i); 69% m.p. 30
C; method (i); 29% m.p. 93
C; method (i); 54% m.p. 41–42
C; method (i); 23%






2-i-Propyl-1,3,4-thiadiazolo-5-onyl. b 2-Phenyl-1,3,4-thiadiazolo-5-onyl. R = cyclohexyl. e NR2 = morpholino. f NR2 = piperidino.

c

2-Cyclohexyl-1,3,4-thiadiazolo-5-onyl.

There are three main synthetic routes.

(i) From thiophosgene and secondary amines or their synthetic equivalents Thiophosgene reacts readily with secondary amines in inert solvents to yield thiocarbamoyl chlorides. The HCl formed in the reaction can be taken up by a further equivalent of the secondary amine without formation of the corresponding thiourea derivatives (cf. Table 5). Alternatively, thiophosgene can be reacted with N-trimethylsilylimide, triphenylphosphinium chloride, or N-trimethylsilyl-1,3-dimethyl-2-imidazoline to effect the same result (Scheme 6). If trialkyl-substituted hydrazines are used instead of secondary amines, the corresponding thiocarbazic acid chlorides (R2NN(R)C(Cl)¼S) result (cf. Table 5) . Thiocarbazic acid chlorides are very useful reagents for the thiocarbazoylation of thiazine-2-ones and thiazolidin-2-ones (Equation (2)).

502

Functions Containing a Thiocarbonyl Group and at Least One Halogen

Me N N SiMe3

N Me

+

–

Ph3P NH2 Cl

S

S CCl2

Ph3P N SiMe3

Ph3P N C

Cl

Me N

S CCl2

S N C Cl

N Me

S CCl2

S Ph3P N C

Cl

Scheme 6

Cl R2N NHR

+

S

CH2Cl2

S C

low temp.

Cl

R2N NR C

ð2Þ

Cl

69%

R = Me

(ii) From tetraalkyl thiuramide disulfides Thiocarbamoyl chlorides have also been synthesized by chlorination of the corresponding tetraalkyl thiuramide disulfides. In addition to elemental chlorine, S2Cl2 has also been employed as a chlorinating agent . The yields are in excess of 70% in refluxing benzene or carbon tetrachloride (Equation (3)). S R2N C

S

S S

C NR2

Cl2 CCl4 80%

S 2R2N C

Cl

ð3Þ

R = Me

(iii) From thioformamides The third method in general use is by the chlorination of thioformamides (obtainable from the corresponding formamides by application of Lawesson’s reagent) using chlorine, SCl2, or SO2Cl2 as the chlorinating agent. Both aliphatic and aromatic thiocarbamoyl chlorides can be obtained employing this method (Scheme 7).

Me Ar N CH O

Lawesson’s reagent

Me

SO2Cl2/Et3N

CH S

CCl 4 Ar = Ph 78%

Ar N

Me Ar

N C S Cl

Scheme 7

6.17.2

6.17.2.1

FUNCTIONS CONTAINING AT LEAST ONE CHALCOGEN FUNCTION (AND NO HALOGEN) Thionocarbonates (O,O-Diesters of Thiocarbonic Acid)

As thiocarbonylating agents for the esterification of alcohols and phenols, in addition to thiophosgene, alkyl- as well as aryl chlorothionoformates and thiocarbonyldiimidazole have been

Functions Containing a Thiocarbonyl Group and at Least One Halogen

503

employed, the latter under especially mild reaction conditions. The yields obtained are generally good. Table 6 lists the properties and starting materials for the syntheses of selected thionocarbonates. The main synthetic routes are given as follows.

Table 6

O,O-Diesters of thiocarbonic acid—starting material and properties O,O-Diesters of thiocarbonic acid

Starting material PMB

Boc N OH

Properties

Yield (%)

References




[]D +43.7
() []20 D 7.3
(+) []20 +5 D

84 69 77



R = Boc, colorless oil;
[]20 D +10.2 ; NMR

71



R = Bzl, colorless oil;
[]20 D +37.2 ; NMR

89

Pale yellow oil;
[]20 D 6.7

82



m.p. 106–108
C

87





OH

OH Si OH

HO HO

COOEt N R

Br PvO

Cl O

OH OH

OH HO O

6.17.2.1.1

OMe

From thiophosgene

Both monohydroxy alcohols and cis-diols react readily with thiophosgene to form the corresponding O,O-diesters (cf., e.g., Scheme 8 ). This method especially (conditions: Cl2C¼S, CH2Cl2, dimethylaminopyridine, 0
C to 10
C) has been employed for the diastereoselective synthesis of the O,O-diesters of a number of diols with complete retention of the configuration(s) present in the diols. Very often, the thionocarbonate group serves as an intermediate or protective group which can be easily converted into the corresponding alkene by Corey–Winter elimination . Often, thionocarbonates (but also other derivatives of thiocarbonic acid) have been produced as intermediates in the course of the deoxygenation of alcohols. For the deoxygenation

504

Functions Containing a Thiocarbonyl Group and at Least One Halogen

BnO O OH

Me O Me

O

CSCl2 PhOH Pyr CH2Cl2

S C BnO O O

OPh Me

BnO O Me O

O Me

O

Me

O

S HO

O

OH

O

CSCl2 DMPD CH2Cl2 –10 °C 66–71%

Scheme 8

of C(2) of a protected L-arabinose, the secondary hydroxyl was reacted with several different reagents to obtain various radical precursors, which were further treated under normal free radical deoxygenation conditions to yield the deoxygenated product (Scheme 9).

BnO O OH

Me

Reagent

BnO O

BnO O OR

O

O

O O

Me

Me

Me

O

Me

O

Me

R = C(S)SMe, C(S)NHPh, C(S)Im2 , C(S)OPh

Scheme 9

The best yields were obtained for the S-methylxanthogenate, though the high flammability of CS2 limits the use of this method to small-scale syntheses. The other reagents tested (PhN¼C¼S, C(S)Im2 and PhOC(S)Cl) did not yield promising results, either because they were insuffficiently reactive or the reagents utilized were too expensive. The most efficient deoxygenation was achieved by preparing the phenoxythiocarbonylester (R¼C(S)OPh) in situ (phenol/pyridine in anhydrous CH2Cl2 was treated with thiophosgene) which was then directly reacted with the secondary alcohol .

6.17.2.1.2

From chlorothionoformates

Addition of phenyl chlorothionoformate [PhOC(S)Cl] to solutions of secondary alcohols (e.g., in dry acetonitrile) led to the isolation of the corresponding thionocarbonates in good yields which were readily reduced to the dehydrogenation product. This method has widely been employed in different types of compounds (cf. Table 7). In a number of cases, the thionocarbonates were not isolated (Equation (4)).

Table 7 Compound

Synthesis and properties of phenylthiocarbonates synthesized from the corresponding secondary alcohol Synthesis

Properties; yield

References

OMe OR' OR' RO

OR' O S

PhOC(S)Cl/pyridine CH2Cl2 20
C

Colorless foam, 1 H, 13C, IR, MS; 94%



N,N-Dimethylaminopyridine/ (DMAP)/acetonitrile/ PhOC(S)Cl rt

Yellow foam, 1 H, 13C, MS; 58%



Pyridine/CH2Cl2 DMAP/PhOC(S)Cl; rt

Light yellow foam, 1 H, 13C; 86%



OPh

N CH N(CH3)2 NH O Si O Si

O

O

N

O

O O

S O

N(i-Bu)2 N N

N

O N O Si O Si O O

N

S O

ODPC

Table 7 (continued) Compound

Synthesis

Properties; yield

References

CO2Me

S O

OPh S

OH

H H

O

H O H O

O

H

H

O

Pyridine/DMAP acetonitrile PhOC(S)Cl rt

1:1 mixture of diastereomers
[]29 D +25.5 C (CHCl3) IR, 1H, 13C; 66%



Acetonitrile (Ar) PhOC(S)Cl rt

Colorless foam UV, 1H, MS; 62/82%



Pyridine/CH2Cl2 0
C PhOC(S)Cl/pyridine

Colorless viscous oil 1 H, 13C; 75%



R

HO O RO O



OR

OAc

O

Red oil/E/Z isomers TR, 1H, 13C, MS; 82%

OR

OH H

S

Pyridine/THF/DMAP/ PhOC(S)Cl; 0
C

S

RO S

OR O OPh

OPh

O

O

S

S H

O

H

OH

H OR

O H

H

OR

H

O OR

O H

H

OR

O

Si

O

Base

O O

S

R O Si

O

PhOC(S)Cl DMAP/acetonitrile (Ar)

m.p. 73–80
C IR, 1H 77%



PhOC(S)Cl/pyridine/ DMAP/CH2Cl2

Colorless oil 1 H, IR, MS 85%



PhOC(S)Cl DMAP, acetonitrile

Colorless oil 1 H, MS; 27%



Pyridine (Ar) acetonitrile DMAP, 0
C

Yellowish oil 1 H, 13C, MS (FAB) 88%



H

O C S OPh

H O R

H N

O RO O O

S

O

N

C PhO RO

O HN N O PhO C O S

O Si(i-Pr)2 O O Si (i-Pr)2

508

Functions Containing a Thiocarbonyl Group and at Least One Halogen R

R

R'

R' CH O C S PhO

+ PhO C(S)Cl

CH OH

RCH2R'

ð4Þ

The HOC(2) group of the ortho-ester of myo-inositol acts as an H-bond donor in a bifurcated, intramolecular H-bond, and the HOC(4) and HOC(6) groups form a strong intramolecular H-bond with one of them acting as a donor and the other as an acceptor. This leads to markedly different nucleophilicities for the three HO groups; the C(4) hydroxy group can be selectively monothiocarbonylated by 4-O-tolylthiochloroformate. The regioselectivity of this acylation is evident from the lack of symmetry expressed in the 1H NMR spectrum of the resulting thionocarbonate (Equation (5)). Bu

Bu H O O O

O O

O O C(S)Cl

CH3

+

HO

HO

O H O H

O

ð5Þ O

C S

CH3

In the course of the -deoxygenation of ()-detoxinine, a ()-hydroxylactam was converted to the corresponding thionocarbonate in 85% yield, again employing phenyl chlorothionoformate, which also permitted a convenient determination of the enantiomeric purity (>99% ee by chiral HPLC) (Equation (6)). O

O N

HO

PhO

H

i-Pr Si i-Pr

O

C(S)Cl

N

S C OPh H i-Pr Si i-Pr

O

ð6Þ O

Thionocarbonates have been successfully used in radical-initiated deoxygenation reactions in carbohydrate derivatives. Phenyl thiocarbonates are well suited because of the high reactivity of PhOC(S)Cl with secondary alcohols and because the resulting thionocarbonates undergo clean photolytic cleavage. Photolysis yields the allylic product stereochemically pure (71–78%) (Scheme 10).

O

O

B

i-Pr2Si O

OH

O

Si i-Pr2

UV

CH

CH2

O

O

O

i -Pr2Si O Si i -Pr2

Scheme 10

O

B

i -Pr2Si

DMAP CH2Cl2, rt

O Bn3Sn2CH2

O

PhO–C(S)Cl

B

O Si i -Pr2

O C O PhO

509

Functions Containing a Thiocarbonyl Group and at Least One Halogen 6.17.2.1.3

From thiocarbonyldiimidazole

Thiocarbonyldiimidazole reacts with alcohols and 1,2-diols forming acyclic or cyclic thiocarbonates, respectively (COFGT (1995)). Examples of the formation of a thionocarbonate (which was reduced with tributyltin hydride and AIBN in an ensuing step) from thiocarbonyldiimidazole and a secondary alcohol or a 1,2-diol are the following (Scheme 11).

S CH3O

CH3O

OH

N

N

N

N

O

S

CH3

O

O

CH3

O

OCH3

N

Then MeOH 36%

N

O

/DMF

N H

N H

S N OH OH O

O

N

N

N O

DMF 95%

R

O

O

S

O R

Scheme 11

The same procedure for the syntheses of various thionocarbonates has been employed for other 1,2-diols . Additionally, cyclic thionocarbonates can be used for protecting glycols and possess similar properties as carbonates, i.e., they are stable in acidic media but are converted to the starting diols in basic media by hydrolysis. Phenyl 2,3-O-thionocarbonyl-1-thio--L-rhamnopyranosides (readily prepared from 2,3-diols in the presence of thiocarbonyldiimidazole, yield 81%) by the action of methyltrifluoromethanesulfonate (MeOTf) afforded the 3-O-(methylthio)carbonyl-2-S-phenyl-2,6-dideoxy--L-glucopyranosides (ready precursors of the corresponding 2-deoxy--glycosides) in high yields (Scheme 12).

S SPh

SPh O

RO HO

OH

N

N

N

N

O

RO O THF S

O

MeOTf ROH

O

RO

OR SPh

O S MeS

Scheme 12

More specialized methods for the syntheses of thionocarbonates have been reviewed elsewhere (COFGT (1995)).

510 6.17.2.2

Functions Containing a Thiocarbonyl Group and at Least One Halogen Dithiocarbonates (Esters of Dithiocarbonic Acid)

Dithiocarbonic acid [S¼C(OH)SH] cannot be isolated as it decomposes spontaneously. The mono-O-esters also decompose readily, especially in acidic media, but are sufficiently stable to enable isolation at low temperatures and to be analytically characterized. The salts (xanthates) are stable but the synthetic efforts within the review period mainly concentrated on the chemistry of the corresponding diesters (COFGT (1995)).

6.17.2.2.1

Salts of O-alkyl esters of dithiocarbonic acid (xanthates) and bisalkoxythiocarbonyl disulfides

Usually the sodium or potassium salts (e.g., ROC(S)SK+) were synthesized. These xanthates were prepared from the corresponding alcohols ROH, CS2, and KOH using the same alcohol as solvent if possible. Practically all alcohols, including starch and cellulose, react (COFGT (1995)) (Equation (7)).

ROH +

CS2

S C

KOH

+

RO

–

S K

+

+

H2O

ð7Þ

The xanthates have been used as precursors for the synthesis of dithiocarbonic acid diesters, and for this purpose, within the review period, only the compounds with R = Et or i-Pr had been employed. The synthesis, spectral characterization, and X-ray structures of methylmercury(II) xanthates (MeOC(S)SHgR, R = Me, Et, i-Pr or Bn) have been reported . These compounds tend to form supramolecular, self-assembled, tape-like arrays in the solid state, whereas the compounds with R = Et or i-Pr form double chains, and the compound with R = Bn forms dimeric units that do not interact with one another. Within the review period, bisalkoxythiocarbonyldisulfides [ROC(S)SSC(S)OR] have been employed as precursors for the synthesis of dithiocarbonic acid diesters which are readily available by the oxidation of the alkali metal xanthates (Equation (8)). S C

2 RO

–

S K

+

S C

S C

Oxidation RO

S

S

ð8Þ OR

As oxidizing agents, the halogens, hypochlorite, bromocyan, and K2S2O8 have been mostly utilized, but other reagents have been employed as well. Yields were high and the bisalkoxythiocarbonyldisulfides are considered to be very useful, easy-to-handle reagents (COFGT (1995)). EtOC(S)SK+ in THF/H2O was used to synthesize the analogous bisethoxythiocarbonyl triand tetrasulfides (by the addition of SCl2 and ClSSCl, respectively), which are in use as new sulfur-transfer reagents for the sulfurization of the nucleoside linkage of oligonucleotides (Scheme 13).

S EtO C S – K +

S EtO C S – K +

THF/H2O +S2Cl2

S EtO C S S S S C OEt S

THF/H2O

S EtO C S S S C OEt S

+SCl2

Scheme 13

Functions Containing a Thiocarbonyl Group and at Least One Halogen 6.17.2.2.2

511

O,S-Diesters of dithiocarbonic acid

O,S-Diesters of dithiocarbonic acid have proven to be an invaluable class of compounds which play an important role in free-radical chemistry, such as for the deoxygenation of alcohols, radical cyclization, and isomerization (COFGT (1995)). These methodologies have found wide application in the synthesis of natural products and their analogs by favoring the radical process and suppressing the side reactions.

(i) From alkali salts of O-esters of dithiocarbonic acid For the preparation of the O,S-diesters of dithiocarbonic acid, mostly sodium or potassium xanthates were simply alkylated using common organic solvents (COFGT (1995)); yields ranged from good to excellent. The synthesis of S-vinyldithiocarbonates is not straightforward because nucleophilic substitution at the vinylcarbon is difficult. However, a general method for the preparation is now available: the reaction of potassium dithiocarbonate with vinylphenyliodonium salt in tetrahydrofuran (THF) occurs quickly and in high yield (Equation (9)).

S RO C S – K +

+

R' CH CHI + PhBF 4–

THF rt

R'

CH CH S C OR S

ð9Þ

The reaction is stereospecific and retention of configuration was observed . Though the conversion of tosyl-activated, optically active cyanohydrins with potassium ethoxide-dithiocarbonate as the S-nucleophile under SN2 reaction conditions in dimethylformamide (DMF) was complete after 1 h, it was observed that at least 20% recemization had occurred. Nevertheless, the yields were good (66–70%) (Equation (10)).

Me

O SO2 H R CN

EtO C(S)S – K +

S

DMF, 1 h rt

S

C OEt

R

H CN

R = n-Pr 97/95% ee

37% ee

R= i-Bu

72% ee

95/92% ee

ð10Þ

The nucleophilic displacement of the bromine atom in -bromo--thiobutyrolactone by the O-i-Pr-xanthic group has been achieved in 45 min (cf. Table 8, entry 1) . Using this procedure, a benzotriazolyl-O-ethylcarbonodithioate (cf. Table 8, entry 2) and a alkythioethynyl-O-ethylcarbonodithioate (cf. Table 8, entry 3) were synthesized. The xanthates CH2¼CHCH2CH(SC(S)OEt)CO2Et (from CH2¼CHCH2CHBrCO2Et) and PhC(O)CH(SC(S)OEt)CH2CH¼CH2 (from PhC(O)CHClCH2CH¼CH2) were also produced in good yields in addition to 5-O-Et-xanthomethyltetrazoles from the corresponding 5-chloromethyltetrazole . 7-Cyclohepta-1,3,5-trienylethoxydithiocarbonate has been prepared in 95% yield by coupling tropylium tetrafluoroborate with potassium ethylxanthate in acetonitrile solution (Equation (11)) (Table 9a).

512

Functions Containing a Thiocarbonyl Group and at Least One Halogen Table 8 Synthesis and properties of O,S-diesters of dithiocarbonic acid

Entry

Synthesis; yield (%)

O,S-diester

–

EtOC(S)S K

S C(S)OEt O

Stable orange oil IR, 1H, 13C



White crystals m.p. 72
C 1 H, 13C



Viscous liquid, cherry color IR, 1H



Yellowish oil IR, 1H, 13C



m.p. 41
C 1 H, 13C



O

S S

References

+

Br

1

Properties

Acetone, rt, 45 min; 100%

N N

N N

S

N N

CH2Cl

OEt +

–

2

EtOC(S)S K Acetone, rt, 4 h;

S

99%

–

RO C(S) K

EtS S C C S C(S) OEt

3

+

DMSO EtS C CCl rt, 60%

(EtOC(S)S)2

4

Me Me C N NC

Me S Me C S C Me OEt

2

Cyclohexane 3–4 h, reflux; 87%

(EtOC(S)S)2 N

5

CN

N N NC CN

2

Toluene 3–4 h, reflux; 87%

OEt S +

–

BF4

EtO C(S)S – K + Acetonitrile 0 °C, 4 h

S

ð11Þ H

95%

Both 1H and 13C NMR spectra indicate the pseudoaxial positioning of the ethoxydithiocarbonate group (1 structure) and the fast, reversible migration of the ethoxydithiocarbonate group along the perimeter of the cycloheptatriene ring that occurs through a series of [1,7]-sigmatropic shifts (
G# (298 K) = 17.4–17.9 kcal mol1).

Functions Containing a Thiocarbonyl Group and at Least One Halogen

513

Table 9a Synthesis and properties of S-alkylcarbonyl xanthates S-alkylcarbonyl xanthate

Properties

EtO C(O) C(S)OEt

Bright yellow oil

C16H33O C(O) C(S)OEt

Bright yellow oil

O C(O) C(S)OEt

Bright yellow oil

Bright yellow oil

O C(O) C(S)OEt

O C(O) C(S)OEt

Bright yellow oil

C8H17 S EtO C S O

Pale yellow solid m.p. 88–89.5
C []D +9.7
, IR, 1H; yield 79%

H O

H O O C

OEt S C S

H AcO

Pale yellow solid m.p. 77.5–79.5
C []D 31
, IR, 1H; yield 52%

H

S C O

Yellow solid m.p. 133–134
C []D +38
IR, 1H; yield 48%

EtO C S Source: .

The reactions of isomeric tetrachlorocyanopyridines with potassium Et-O-dithiocarbonate have also been studied: tetrachloro-2-cyanopyridine was converted successively into the 4-mono- and then the 3,4-bisethylxanthates; with additional potassium Et-O-dithiocarbonate, the last derivative undergoes intramolecular cyclization with formation of 1,3-dithiolo[4,5-c]pyridine . For the other polychloromonocyanopyridines, substitution of the chlorine atoms by the ethylxanthate fragment was observed, sometimes accompanied by the loss of COS instead of heterocyclization . New S-alkylxanthates have been synthesized via the S-alkoxycarbonyl xanthates ; the latter compounds were obtained from the corresponding alcohols by the dropwise addition of a solution of phosgene in toluene and the crude alkylchloroformates that formed (obtained in near quantitative yield) treated with potassium O-ethylxanthate in acetone. Finally, upon exposure of these yellow-colored S-alkoxycarbonylxanthates to visible light in an inert solvent under reflux, a smooth rearrangement took place affording the S-alkylxanthates in good yields (see Table 9a) (Scheme 14) (Table 9b). When 5-hexenyloxycarbonylxanthate was irradiated under the same conditions, a cyclopentane derivative was isolated. S-alkoxycarbonylxanthates derived from various substituted 3-buten-1-ols behaved similarly, affording the corresponding lactones in all cases .

514

Functions Containing a Thiocarbonyl Group and at Least One Halogen

R

ii. EtO C(S)S K

O S

R1 R3

S

O

hν

S S

OEt

S

hν

R

OEt

hν Toluene reflux

OEt

O

O

S

S C

S

O

R2

O

i. COCl2

R OH

OEt

S OEt

S C O

Toluene reflux

S

S OEt

R2

O R1

R3

Scheme 14

Table 9b Synthesis and properties of S-alkyl xanthates S-alkyl xanthate

Properties

EtS C(S) OEt

Yellow oil

C16H33S C(S) OEt

Yellow oil

S C(S)OEt

S C(S)OEt

S C(S)OEt

S C S

H

EtO

Colorless liquid, IR, 1H; yield 61% Colorless liquid, IR, 1H; yield 59% Colorless liquid, (2:1 (E)/(Z))IR, 1 H; yield 52% White solid (4:1 mixture of epimers), 3-isomers: m.p. 103-106
C,[]D+30, IR, 1H; yield 71%

S S C OEt

White, crystalline solid,m.p. 185–186
C,[]D 26, IR, 1H; yield 83%

H

Colorless oil,[]D +57, IR, 1H; yield 92%

S C S EtO S S C OEt

Source: .

Colorless oil, IR, 1H; yield 87%

Functions Containing a Thiocarbonyl Group and at Least One Halogen

515

Potassium O-furfuryl dithiocarbonates have been employed as reactive intermediates for a simple synthesis of furfuryl sulfides via extrusion of COS .

(ii) From bisalkoxythiocarbonyl disulfides For the preparation of carbohydrate-derived S-xanthates which are attractive due to their importance as precursors for osides or anomeric activators (i-PrOC(S)S)2 was used. The introduction of the S-xanthate group was regiospecific and led to reasonable yields with reaction at the primary and anomeric hydroxyls of the sugars (Scheme 15).

HO Oside

HO

Oside

i -PrOC(S)S

Bu3P, (i -PrOC(S)S)2

Carbohydrate

i -PrOC(S)S

Bu3P, (i-PrOC(S)S)2 Toluene, 1 h

Toluene, 1 h

Carbohydrate

Scheme 15

A complete selectivity for the primary hydroxyl site was observed for diol substrates possessing a secondary hydroxyl function, though the reaction appeared to be quite sensitive to steric effects. The direct conversion of the anomeric hydroxyl into O-alkyl, S-glycosyl dithiocarbonates in high yield reveals the efficiency of the method . A number of sterically hindered tertiary S-alkyldithiocarbonates were synthesized by the decomposition of tertiary diazoderivatives (which can easily be made from the corresponding ketone hydrazones) in the presence of dithionosulfides in good yield (cf., e.g., entries 4 and 5 in Table 8) (Equation (12)). R1 R1 R 2 C N N C R2 E E

(ROC(S)S)2 ∆, –N 2

S R1 R2 C C E OR

ð12Þ

Two malonate xanthate derivatives were synthesized directly by reaction of the enolates of the starting materials with diethyldithiobis(thioformate) (Scheme 16).

COOEt

i. LDA, THF –78 °C ii. (EtOC(S)S)2

COOEt S

0 °C 58%

COOEt COOEt

i. NaH, DMSO benzene ii. (EtOC(S)S)2 rt 50%

EtOOC

C S

OEt

COOEt S

C S

OEt

Scheme 16

This is a direct way of transforming carbanionic centers into proradical ones, resulting in the ‘‘Umpolung’’ of active methylene compounds.

516

Functions Containing a Thiocarbonyl Group and at Least One Halogen

(iii) From carbon disulfide The preparation of O,S-dithiocarbonates directly from the alcohols by reaction with a base, CS2, and a haloalkane has been used widely (COFGT (1995)). In the typical reaction procedure, the alcoholate is produced with NaH in THF, and catalytic amounts of imidazole, CS2, and the halomethane are then added sequentially. A number of applications of this procedure have been reported after 1995. 2,2-Dimethyl-1,3-dioxan-5-ols have been converted into the corresponding methoxydithiocarbonates in good yields in the course of highly diastereoselective and enantioselective syntheses (de  98% and ee = 92–98%) (Equation (13)). S OH R2 O

O

i. NaH ii. CS 2

R1

iii. MeI

O

SMe R1

R2 O

ð13Þ

O

82–93% R1, R2 = Me, Et, i -Pr, Bn, CH2OBn, CH2O(CH2)2TMS

Employing the same procedure, S-propargylxanthate (BnOC(S)SCH2CCH) was synthesized from benzyl alcohol using propargyl bromide as the alkylating agent . A tricyclic sulfide with C2 symmetry was synthesized via a radical-mediated route from the xanthate (prepared in excellent yield of 90% from the corresponding dibenzylidene acetal) using tributyltin hydride in toluene and ,-diazoisobutyronitrile as initiator (Scheme 17). The 3-O-xanthyl-1,2-cyclopropylglucal derivative, synthesized similarly from the corresponding secondary alcohol, was used for the formation of 1-C-methyl-2,3-unsaturated sugars via tri-nbutyltin hydride-mediated ring opening . Ph OH O

O

O

O

OH

Ph

O O HO

O

Ph

SMe NaH THF CS2 MeI rt 90%

NaH THF CS2 MeI rt 87%

S O

O

O

O

Bu3SnH AIBN Toluene 80 °C, 16 h

O

O

Ph

O

O

Ph O

O S

S Ph

MeS

O O MeS C O S

78%

O

Bu3SnH AIBN

O O

O Me

Benzene reflux, 2 h (α )D 63° 67%

Scheme 17

Other O,S-dithiocarbonates have been synthesized using the NaH/CS2/MeI method as suitable precursors for radical group transfer azidation , for an intramolecular carbocyclization in the course of the total synthesis of (+)-eremantholide A and ()-verrucatol , for the O,S-dithiocarbonates , for the deoxygenation of primary and secondary alcohols in the course of the total syntheses of macrolide antibiotics and (R)-()-2,4-diphenylbutyric acid , and for the synthesis of trifluoromethyl ethers by oxidative desulfurization– fluorination of the trifluoromethylated xanthates (cf. Table 10) . Allyl alcohols adsorbed on Al2O3KF at room temperature reacted with CS2 and methyliodide to provide the S-allyl-S-methyl-dithiocarbonates (R1R2C¼CHCR3OC(S)SMe) . Yields were in excess of 50%, and the products, yellow liquids, were characterized by 1H and 13 C NMR and MS.

517

Functions Containing a Thiocarbonyl Group and at Least One Halogen Table 10 Synthesis and properties of S-aryl and S-alkyl xanthates S R O C SMe

Compound

Yield (%)

Properties

4-Me–C6H4– 4-Br–C6H4–CH2CH2– n-C16H33 –

Pale yellow oil IR, 1H, MS

82

Pale yellow oil IR, 1H, 13C, MS

99

Pale yellow oil IR, 1H, 13C, MS

88

OCS2Me

OCS2Me

Br OCS2Me

Pale yellow oil IR, 1H, 13C, MS

97

Pale yellow needles m.p. 106–107
C IR, 1H, MS

91

Pale yellow oil IR, 1H, 13C, MS

99

(iv) From CS2 and methyl iodide 1-(Methyldithiocarbonyl)imidazole, a yellow oil that has been characterized by 1H NMR, was produced by the reaction of imidazole with CS2 and methyl iodide in the presence of sodium hydride (vide supra). Xanthates result from the reaction of alcoholates (deprotonated using NaH in THF) directly with 1-(methyldithiocarbonyl)imidazole at room temperature (Equation (14)).

N

+

–

N

Na

i. CS2,THF, 0 °C ii. MeI

S N

98%

Base R-OH

N C SMe

S RO C

ð14Þ

SMe

>95%

The conversion of alcohols to O-alkyl, S-methyl dithiocarbonates using 1-(methyldithiocarbonyl)imidazole proceeds efficiently; primary, secondary, tertiary, benzylic, and aromatic alcohols all reacted to provide products in high yields (>95%).

(v) By radical addition to alkenes O,S-Diesters of dithiocarbonic acid added efficiently to unactivated alkenes by a radical mechanism to provide the corresponding adducts (Scheme 18).

R

S

S C

OR'

Initiator

R''

R'' R

R

R

S

S C

R'' OR'

S R

S C OR'

Scheme 18

When trifluoromethyl xanthates were employed, the trifluoromethyl group added to the least hindered site of the alkene . The xanthate methodology is applicable for additions to strained alkenes such as cyclobutenes, azetines, and cyclopropenes .

518

Functions Containing a Thiocarbonyl Group and at Least One Halogen

The intermolecular addition of the radical obtained from the xanthate to suitable allylic or homoallylic amines proved to be the key step for the construction of various nitrogen heterocycles . By the same procedure, the electrophilic alkyl radicals served as useful precursors for annulation reactions and afforded cyclopentane derivatives in moderate-to-good yields . Substituted S-phenacyl xanthates add intermolecularly to various alkenes and sterically hindered xanthates, and by the same process, add to allyl acetates and allyltrimethyl silane and to allyl- and vinylboronates to provide the expected products. The synthesis of benztriazole xanthates has been realized using a clean, efficient, and nontoxic xanthate radical process (Scheme 19). N N N CH2 Cl

EtOC(S)S – K Acetone 20 °C, 4 h

Peroxide or hν R

N

+

N N

CH2

S

OEt S

N

N

N

N

N

N CH2

CH2

CH2

R CH S C S EtO

Scheme 19

The addition of the benzotriazol-1-yl methyl radical was observed to be regiospecific with the benztriazol-1-yl methyl moiety adding to the unsubstituted side of an alkene double bond. The existence of the radical could not be proven by ESR spectroscopy, but by-products which could only originate from the formation of the benzotriazol-1-yl methyl radical strongly implied the existence of such.

(vi) By other methods A novel and convenient preparation for steroidal 1,3-oxathiolane-2-thiones (cis cyclic dithiocarbonates) at room temperature in high yields has been reported by the reaction of steroidal 5,6epoxides with CS2 in THF using lithium bromide as catalyst (Equation (15)). C8H17 CS2, LiBr THF, rt 70–83%

R

ð15Þ

R O

O

S S

R = H, OAc, Cl

The cis products were obtained selectively as the sole products. The reactions of various oxiranes with CS2 under the same reaction conditions have also been examined . The desired dithiocarbonates were obtained regioselectively in high yields, and the formation of the regioisomeric trithiocarbonates and episulfides was suppressed (Equation (16)). S

S O R

CS2

O

S

S

Cat. R

R

S O ,

S R

S ,

S

ð16Þ

R

The selectivity and yield of the reactions were strongly reduced when other alkali halides were applied as catalysts . Using this method, 4-arylspiro[1,3-oxathiophene-2-thione]5-tetral-1-one was prepared .

Functions Containing a Thiocarbonyl Group and at Least One Halogen

519

A facile, one-pot synthesis of a number of insecticidal thiophosphoryl xanthates was performed using the mild base 1,8-diaza[5,4,0]bicycloundeca-7-ene in the DBU-catalyzed sequential reaction of various alcohols ROH (R = allyl, i-Bu, n-Bu, s-Bu, 2-Ph-ethyl, furfuryl; all in excess) with CS2 and diethoxyphosphoryl chloride (Equation (17)).

DBU, CS2

R OH

R O

0 °C

S C

SH

S

ClP(S)(OEt)2

R

rt

O

S P OEt S OEt

ð17Þ

65–88%

The catalyst in this reaction is mild and can be removed from the reaction mixture simply by washing with water. Another mild, chemoselective, and efficient protocol for the thiocarbonylation of alcohols and the thiocarbamation of amines has been reported using CS2 and alkyl halides in the presence of caesium carbonate and tetrabutylammonium iodide (TBAI) (Scheme 20).

R OH +

R NH2

R' X

+

R' X

S

CS2, CsCO3, TBAI R

DMF, 0 °C to rt

O

CS2, CsCO3, TBAI

R'

S R

DMF, 0 °C to rt

S

N H

S

R'

Scheme 20

For the syntheses of various arylseleno- and aryltellurothionoformates (PhOC(S)SeAr and PhOC(S)TeAr, respectively), commercially available phenyl chlorothionoformate was reacted with (Me3Si)3SiSeAr and (Me3Si)3SiTeAr, respectively, and 4 mol.% of tetrakis(triphenylphosphine)palladium. Yields were excellent, 86–96% after chromatography, and the products were identified unequivocally by 125Te and 77Se NMR .

6.17.2.2.3

Sulfoxides of O,S-diesters of dithiocarbonic acid (sulfines)

Xanthates have been oxidized using MCPBA in CH2Cl2 at 0
C (Equation (18)). O

S R1O

MCPBA SR2

CH2Cl2

S

R1O

S SR2

(E )

+

R1O

O SR2

ð18Þ

(Z )

NMR analysis of the sulfines (performed rapidly after reaction) showed that the (E)-isomer was predominantly obtained (R1 = i-Pr, R2 = Bn), revealing that oxygen transfer occurs to the opposite side of the SR2 group. However, for another sulfine (R1 = 2,6-di-t-Bu-phenyl, R2 = Me), the same analysis yielded the reverse result with an (E):(Z) ratio of 8:92. This sulfine could be kept without change for months at ambient temperature in contrast to the preceding one which transformed into a mixture of thiocarbonate and dithioperoxycarbonate upon standing. The sulfine structure was determined by X-ray analysis which provided a C¼S bond length of 1.669 A˚ and an S¼O bond length of 1.506 A˚. The plane of the sulfinyl group is perpendicular to the plane of the phenyl ring and the C(7)–(S(2) bond has an s-trans arrangement in contrast to the s-cis conformations of esters, thioesters, and dithioesters .

520 6.17.2.3

Functions Containing a Thiocarbonyl Group and at Least One Halogen Thiocarbamates (Esters of Thiocarbamic Acid)

The free thiocarbamic acids (H2NC(S)OH and its analogs) cannot be isolated because they decompose spontaneously to COS and the corresponding amine, but their salts have been prepared (COFGT (1995)).

6.17.2.3.1

From O-alkyl or O-aryl chloroformates and amines

By reacting the easily available thiocarbamic ester chlorides with primary and secondary amines, the thiocarbamic acid O-esters can be synthesized. Inert solvents, e.g., chloroform or THF, were used, sometimes in the presence of a base for neutralizing the HCl produced. By this procedure, aryl thiocarbamates (for the further synthesis of caffeic acid) were readily obtained (Scheme 21).

NH2

H N

S PhO C

OPh

Cl S

R

R THF rt H N O

S

R1

PhO C Cl

R2

O

S C OPh N R1 O R2 O

Scheme 21

Similarly, by using pyridine as the base, isoxazol-5(2H)-ones were reacted with thiocarbamoyl chloride (and with various other thiocarbonyl chlorides) to provide the N-thioacetylated derivatives in moderate-to-good yields and with the formation (5%) of the competing O-thioacetylated isomer . To overcome the side reactions of the chloroformates, tertiary aliphatic amines were dealkylated (Scheme 22).

S R3N

PhO

S

CH2Cl2

+ Cl

(N2), 1 h

PhO

NR2

+

RCl

70–95% R3 = Me3, Et2Bn, Me, morpholine, Me2cinnamyl, quinuclidine, tropine, bicuculline, Me2t-Bu

Scheme 22

Instead of chloroformates, the corresponding bis(ethoxythiocarbonyl)sulfide was employed to synthesize the thiocarbamates of glucosamines and the dithiasuccinoylamino protecting group for the solid-state synthesis of peptide nucleic acids .

Functions Containing a Thiocarbonyl Group and at Least One Halogen 6.17.2.3.2

521

From N,N-dialkylthiocarbamoylchlorides and alcohols or phenols

This reaction proved to be another general method to prepare the corresponding thiocarbamates by the reaction of alcohols with N,N-dialkylthiocarbamoylchlorides (COFGT (1995)). Further examples of this method have been published after 1995. The 1:2 mixture of diastereomeric meso- and rac-diols was converted into the corresponding dithiocarbamates in good yield with retention of the diastereomeric ratio; the pure mesocompound yielded only the meso-dithiocarbamate (Equation (19)). S OH

i. NaH, THF

R

Me2N

R

ii. Me 2NC(S)Cl

OH

ð19Þ

O C S Me2N

77–89% R =C

O

CH, Me

A number of thiocarbamates of 5-O-benzyl-1-O-methylribofuranoside were synthesized by the reaction of the sodium salt with several thiocarbamoyl chlorides in THF. Yields were in excess of 80% and the thiocarbamates were employed as glycosyl donors for the stereoselective synthesis of -D-deoxyribonucleotides. The best result, : = 4:96, was obtained for the diethylcarbamate . In the above reaction, the -side of the glycosyl donor, was efficiently blocked by the O-thiocarbamoyl group and the reaction proceeded under the remote stereocontrol of the O-thiocarbamoyl directing group (Equation (20)). Bn

O

i. NaH, THF, rt

Bn

O

OMe

OH

ii. R2NC(S)Cl

O

OH NR2

ð20Þ

S NR2 = NEt, NMe2 , N

O

Many more phenol derivatives have been reacted by this procedure (cf. Table 11). In one case , the thiocarbamate of a cross-conjugated cyclopentenone derivative was synthesized (Scheme 23).

6.17.2.3.3

From N,N 0 -thiocarbonyl diimidazole and alcohols

The mild procedure of functionalizing alcohols by employing thiocarbonyl imidazolides as intermediates is a standard procedure these days for the dehydroxylation of secondary alcohols. The yields are high, but only in a few cases the thiocarbonyl imidazolides were isolated (cf. Table 12), otherwise they were used further without purification (Scheme 24).

6.17.2.3.4

From thiophosgene and 1,2-amino alcohols

Cyclization of the 1,2-amino alcohols with thiophosgene and triethylamine in methylene chloride gave an oxazolidinethione in 95% yield as a viscous oil which crystallized after several weeks. The oxazolidinethione was finally acetylated with n-BuLi and n-PrCl in THF at –78
C to provide the propionyloxazolidinethione in 90% yield (Scheme 25). By the same synthetic procedure, ()-(hydroxyoxindol-3-yl)methylammonium chloride was treated with thiophosgene to provide the desired product with a spiro ring system in 92% yield as colorless crystals which were characterized by IR, 1H, and 13C NMR, UV, and MS . Alkylation using methyl iodide, however, provided the S-alkylation product.

522

Functions Containing a Thiocarbonyl Group and at Least One Halogen Table 11 Thiocarbamates obtained from thiocarbamoyl chlorides

Compound Me2N(S)CO C

C

CH

OC(S)NMe2 S Me2NC O

O

O

Synthesis; yield

Properties

References

(a) NaH, THF, 20
C (b) Me2NC(S)Cl, 20
C; 98%

meso m.p. 134
C, 1H, IR rac m.p. 89–90
C, 1 H, IR



(a) NaH, DMF (b) Me2NC(S)Cl, 96%

m.p. 103–104
C MS, 1H, 13C



(a) NaH, DMF (b) Me2NC(S)Cl, rt; 83%

Yellow solid m.p. 126
C IR,1H, 13C, MS



ArOH/acetonitrile Me2NC(S)Cl, KF (on alumina); 58%

Red, viscous liquid 1H



Et2N-C(S)Cl, DMAP, TEA, 1,4-dioxane reflux; 71%

Light tan crystals m.p. 73–75
C 1 H, MS



DMF, NaH, Me2NC(S)Cl, 85
C; 80%

Colorless crystals m.p. 132–195
C 1 H



THF(N2), NaH, THF, Me2N-C(S)Cl, rt; 77%

m.p. 79–81
C 1 H



CHO O

NMe2 S

S O

NMe2

S O

NEt2

OMe

S S C NMe2 Me2N C O O

MeO OMe Me OHC

OC(S)NMe2

-D-Mannopyranosylamine also reacted with thiophosgene under the conditions described above, whereby a cis-bicyclic thiocarbamate resulted. The corresponding trans-hydrindane-type isomer, produced from the corresponding -D-glucopyranosyl derivative, was not that stable due to the strain resulting from the ring fusion (Scheme 26). When oligosaccharides were reacted with thiophosgene, the bis[cyclic thiocarbamate]s were the only products that could be isolated .

6.17.2.3.5

From CS2 and 1,2-amino alcohols

This last reaction was also accomplished using CS2/triethylamine in THF; however, the yields were lower (Scheme 27).

Functions Containing a Thiocarbonyl Group and at Least One Halogen S

S Ar – OH

+

R2N C

523

Ar O C

NaH, DMF, rt

NR2

Cl

O

O

OEt

HO

Me2N C(S) – Cl

+

O

O CH2Cl2 DABCO 0 °C

OEt

O

Me2N

S

84%

Scheme 23

The relative configurations of the vicinal hydroxy and amine substituents of -hydroxyhistidine derivatives were determined by transformation into the corresponding oxazolidine-2-thiones using CS2/TEA. The cis or trans configuration was easily determined by 1H NMR; for a cis stereoisomer JH,H lies in the range 8–9.5 Hz, and for a trans arrangement JH,H lies in the range 5–8 Hz . Other 2-oxazolidinethiones have also been synthesized employing this synthetic procedure (cf. Table 13) . The corresponding six-membered, 2-thiono-1,3-O,N-heterocycles were also produced by reaction of the corresponding amino alcohols with carbon disulfide in the presence of trimethylamine at room temperature (Scheme 28). The cis or trans configuration of the ring anellation of the two six-membered rings follows from the values of the J-couplings of H-8a (two 3Jax,ax couplings are observed in the case of the trans isomer but only one in the case of the cis isomer). The corresponding oxazolo[4,5-b]pyridine-2(3H)-thione was synthesized by the reaction of 2-hydroxy-3-aminopyridine with potassium ethylxanthogenate ; the thione structure of the compound was established by both 1H NMR and X-ray diffraction.

6.17.2.3.6

From isothiocyanates and alcohols

The addition of alcohols to isothiocyanates is useful as another general method for the preparation of O-alkyl thiocarbamates. Some examples of the procedure that have been reported include (cf. Table 14) (Equation (21)).

R N C S

EtOH

∆

S R NH C

ð21Þ

OEt

Triethylamine and sodium alcoholates were found to strongly accelerate the reaction. Phenols only add poorly to the phenyl isothiocyanates. The S-alkyl esters of N-alkyl(aryl) dithiocarbamic acid were converted into the corresponding O-alkyl(aryl)esters of N-alkyl(aryl)thiocarbamic acid using alkali metal alkoxides in the presence of one or more alcohols as solvents . In the presence of base, the formation of a six-membered cyclic thiocarbamate is slow, resulting from intramolecular nucleophilic addition of the C(5) hydroxyl group to the heterocummulene functionality of the furanose form, was observed (Equation (22)).

524

Functions Containing a Thiocarbonyl Group and at Least One Halogen Table 12 Thiocarbonylmidazoyl derivatives obtained from the corresponding secondary alcohol

Compound N

POPh2 N

C S

O

POPh2 N

N

C S

O

Me

Properties; yield

References

cis: While solid, m.p. 192–193
C, IR, 1H, 31P, MS; 65% trans: Brown solid m.p. 172–173
C IR, 1H, 31P, MS



Pale yellow oil, 1H; 84%



White solid m.p. 135–137
C, MS, 1H; 81%



NOMe

TOS

NH2 N O

O

N

N S

O

O

F

N

Si Si

O C

O

N

COOMe H S C N O

R

N

N

R=H

Pale yellow solid, 1 H, 13C, IR, MS; 85%

R = Me

White solid, 1H, IR; 77%

13

C,



OH

S O O

O

N

N

OTBS

Colorless oil, IR, 1H, 13C, MS; 82%



Colorless oil, IR, 1H, 13 C, MS; 56%



Yellow oil, IR, 1H, 13 C, MS; 89%



Yellow oil, IR, 1H, 13 C, MS; 73%



O S O C N

N

OTBS

S O O

N

N

OTBS

SBTO S O O

SBTO

N OTBS

N

525

Functions Containing a Thiocarbonyl Group and at Least One Halogen N R1 R2

+

CH OH

S C N

S

Benzene, 80 °C NaH reflux

N

R1 R2

CH O

N

N

N

R1 R2

CH2

Scheme 24

S OH

NH2

S CCl2 Et3N CH2Cl2

n-Bu

HO

+

HN

O

–

N

O

S

O O

CH2Cl2

N H

S

n-Bu

S CCl2

O

Me

n-Bu

H N

NH3Cl

O

n-BuLi THF EtCOCl

N H

Scheme 25

S HO HO

OH OH O

HO HO

NH2

O

HO HO

NH2

OH

HO OH

O

H N

S

O

HO HO

NH

OH

OH HO HO

OH O O

O OH

HO O

OH

S CCl2

OH OH

Pyridine

Scheme 26

O H N OH O OH S

O

OH O N

H

S

526

Functions Containing a Thiocarbonyl Group and at Least One Halogen S

HO COOEt N SO2Ph

O

CS2 , Et 3N CH2Cl2 rt

NH

NH2 N SO2Ph

COOEt

S

HO

O COOEt

N SO2Ph

NH2

CS2 , Et3N CH2Cl2 rt

NH N SO2Ph

COOEt

Scheme 27

Table 13 2-Oxazolidinethiones as synthesized from the corresponding -amino alcohols Compound

Synthesis; yield

Properties

O

HOH2C

S N H

References

CS2, H2O2, base; 100%

Colorless crystals m.p. 57.5–59.5
C 1 H



CS2, KOH, Pb(NO3)2, H2O; 20%

White solid m.p. 94
C 1 H, 13C



CS2, KOH, Pb(NO3)2, H2O; 14%

White crystals m.p. 54
C 1 H, 13C, MS



CS2, Et3N, NaOH; 63%

Oil []D 93
1 H



CS2, Et3N, NaOH; 60%

White solid m.p. 142–143
C []D 187.3
1H, 13C



O S N H O S N H O S PhH2C Me Me PhH2C

N H O S N H

HO NH2 Ph H

S CS2, Et3N CHCl3 rt

O NH Ph H

47%

Ph H

OH NH2

CS2, Et3N CHCl3 rt 43%

Scheme 28

Ph H

S O NH

527

Functions Containing a Thiocarbonyl Group and at Least One Halogen Table 14 O-Alkyl thiocarbamates synthesized from the corresponding isothiocyanates Compound

Synthesis; yield

Properties

References

COOEt S

N

S

EtOOC

NH C OEt

EtOH (anh.) reflux; 72%

Yellow crystals m.p. 116–117
C IR, 1H,13C,MS



NaH/MeOH; 0
C; 78%

Pale brown crystals m.p. 103–104.5
C []D 23.1
1 H



ROH reflux; 85%

Red needles m.p. 130–138
C IR, 1H



Ethyleneglycol reflux; 69%

m.p. 205–207
C IR, 1H



NaOMe, ether (N2); 65%

m.p. 48–50
C IR, 1H, 13C



O H N

N

morph F

C S

OEt

S H

N

OEt

+

–

CH3 CF3SO3

HN

S C

OH

O

N S

N

OEt Et CH

S

NH C OMe

RO RO

N C S O OR OR

H DMF Et3N 80 °C 100%

S

N O OH

O

OH

ð22Þ OH

[α] D–35.5°

Isothiocyanates, under Evans conditions (Sn(Otf)2, N-ethylpiperidine) (COFGT (1995)), afforded the syn-aldol which was isolated as an intramolecularly derivatized heterocycle in moderate chemical yield but with syn/anti selectivity (Equation (23)). F NO2 OO

O

i. Sn(OTf )2 N-Et-piperidine

N Bn

N C S

THF ii. 4-F-3-NO2-benzaldehyde

OO

O

ð23Þ

N Bn

O HN S

The photolysis of O-allyl- and O-but-3-enyl-N-phenylthiocarbamates in benzene readily provided the corresponding S-allyl- and S-but-3-enyl-N-phenylthiocarbamates in good yields .

528

Functions Containing a Thiocarbonyl Group and at Least One Halogen

6.17.2.3.7

N-acyl-1,3-oxazolidine-2-thiones as auxiliary agents

N-acyl-1,3-oxazolidine-2-thiones have been employed for auxiliary-based, highly diastereoselective aldol additions. For the enolization, TiCl4/TMEDA , TiCl4/()-sparteine/N-methylpyrrolidine , Sn(OTf)2/N-Et-piperidine in CH2Cl2 (45
C) , or Ti(Cl)4/ DIPA in CH2Cl2 (78
C) (followed by an aldehyde) have all been used (Equation (24)). S O

O

S TiCl4/ – sparteine

N

CH2Cl2, then RCHO

Ph Ph

O

O

S

OH R

N

+

Ph

O

O

N

OH R

ð24Þ

Ph Ph

Ph 92:8 to 98:1

Other 1,3-oxazolidine-2-thiones for the highly stereoselective construction of CC bonds are known (Scheme 29). S O

O N

R

R = Me, Et, Bu, Ph

O O

N S

O N

S

R = Me, Et, i-Pr, Ph, Ph(X)

O

R

Scheme 29

The camphor-based, chiral N-acetyloxazolidinethiones have been used as starting materials for: (i) a one-step enolate bromation–aldolizaton reaction to provide bromohydrins (with yields in excess of 90%; additionally, the asymmetric induction of this reaction was shown to be exceptionally high) ; (ii) a racemizationfree deacetylation of 3-acyl-1,3-thiazolidine-2-thiones ; and (iii) an asymmetric synthesis of -mercapto carboxylic acid derivatives (Equation (25)). OH O i. TiCl4, DIPEA Me

C N

O

6.17.2.3.8

S

R

ii. Br2IPIPEA iii. RCHO

O

N

ð25Þ

Br S

By thermal conversion of 2-allyl thiobenzothiazoles

The thermal conversion of 2-allyl thiobenzthiazoles and O-methyl-S-allyl-N-acridinyl iminothiocarbonates to the corresponding thiones has been reported to occur successfully with yields greater than 60% (Scheme 30). This S ! N allylic rearrangement is the result of a concerted [3,3]-sigmatropic shift.

6.17.2.3.9

Other methods

The oxo groups in 6-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones could be replaced by sulfur by the fusion (melting) of the diones with tetraphosphorus decasulfide (Equation (26)).

529

Functions Containing a Thiocarbonyl Group and at Least One Halogen

N

N

∆

S

S

O

O

OMe

OMe S

∆

N Acr R

S

N

Acr R

Scheme 30

O

O

O

P4S10

N

Cl

+

N

Cl

S R

R

S N

Cl

O

O

O

S

ð26Þ R

The products were isolated in yields below 50% after column chromatography, and the structures were confirmed by IR and 1H and 13C NMR. Cyclic thionecarbamates were usually prepared by the reaction of amino alcohols with CS2 or thiophosgene (vide supra); treatment of 3-hydroxybutylisocyanide with sulfur in the presence of 5 mol.% selenium and Et3N in refluxing THF for 3 h resulted in the formation of 1,3-oxazine2-thione in 79% yield (Equation (27)). OH

R S (5 mol.% Se)

R

NC

HN

Et3N THF, reflux

O

ð27Þ

S

62–89% R = Me, Ph, CH2Cl

Oxazolidine 2-thiones were synthesized from alkenes by employing one-pot Co(II)-catalyzed epoxidation followed by cleavage with trimethylsilylisothiocyanate (Equation (28)). Ph

O

i. Co (II), O2, (CH3)2CH – CHO

Ph Ph

S

ii. Me 3Si – N C S, Co(II)

N H

Ph

ð28Þ

56%

The reaction is highly regio- and stereoselective as only one isomer was obtained and careful analysis of the reaction mixture indicated the total absence of the other regioisomer. The yields of the oxazolidine 2-thiones are improved considerably by using the epoxide instead of the alkene . In an approach to artificial nucleoside synthesis, a sugar-derived 1,3-oxazolidine-2-thione was produced from free or partially-protected sugars in one step using potassium thiocyanate under acidic conditions (Equation (29)).

Sugar

H N

KSCN, HCl, H2O

O

80–100% OH

S O

ð29Þ

OH

The structure of the sugar ring was clearly defined with formation of a furanose ring, confirmed by 1H and 13C NMR, and an anomeric configuration controlled by the hydroxyl located on C(2). Novel, convenient syntheses of 1,3,4-oxadiazol-2-(thi)ones from N-t-Bu-diacylhydrazines have been reported by reaction with t-BuOK followed by treatment with thiophosgene (Equation (30)).

530

Functions Containing a Thiocarbonyl Group and at Least One Halogen O R

N H

But N

R' O

O

i. t-BuOK / THF ii. C(S)Cl 2

R

N

N

R'

O

70–80%

ð30Þ

S

R, R' = alkyl, aryl

6.17.2.4

Dithiocarbamates (Esters of Dithiocarbamic Acid)

The dithiocarbamic acids have been obtained from their alkali metal dithiocarbamates by treatment with HCl. However, they easily decompose in aqueous solution to produce CS2 and the corresponding amines (COFGT (1995)). N,N-diphenyldithiocarbamic acid (m.p. 147
C after recrystallization from benzene) and the N-acyldithiocarbamic acids (2-oxopyrrolidide, m.p. 101–102
C; and 2-oxopiperidide, m.p. 103–105
C), however, are sufficiently stable to permit isolation . Recently, ethoxydithiocarbamic acid [EtO2CNHC(S)SH] was isolated as pale yellow crystals and unequivocally characterized by IR and 1H NMR. Upon standing in the air, it dimerizes to form [EtO2CNHCS2]2.

6.17.2.4.1

Alkali metal salts of N,N 0 -disubstituted dithiocarbamic acid (dithiocarbamates)

Dithiocarbamates are usually prepared from CS2 and 2 equiv. of an amine using common solvents such as acetone or ethanol. When the reaction was performed in aqueous NaOH or KOH (COFGT (1995)), the corresponding sodium or potassium dithiocarbamates were obtained (e.g., sodium 1,10 -ferrocene-bis(dithiocarbamate) or potassium 1,1-dioxothiolan-3-yl-dithiocarbamate ); in ammonium hydroxide solution, the ammonium dithiocarbamate was obtained . The dithiocarbamate anions are good ligands for transition metals and a large number of complexes have been constructed incorporating them. The sodium salts of the dithiocarbamates were normally used, and the complexes obtained ([R2NC(S)S]TeMe2 , [R2NC(S)S]AsPh , [MeC(S)NHC(S)S]M (M = K, Rb or Cs) , [R2NC(S)S]GeClPh2 , [RHNC(S)S]SnCy3 ) were characterized by X-ray diffraction.

6.17.2.4.2

Esters of dithiocarbamic acids

(i) From carbon disulfide and base followed by alkylation The synthesis of the esters of dithiocarbamic acid is conventionally separated into two steps: the first step is the synthesis of the dithiocarbamates by reaction of a secondary amine with CS2 in the presence of a base; the second step is the alkylation of the dithiocarbamate salts, thereby converting them to the corresponding S-esters (Equation (31)). R1 NH + CS2 R2

KOH

R1 S N C – + R S K

MeI –KI

R1 S N C R S Me

ð31Þ

Following this procedure, the methyl esters of various dithiocarbamates were synthesized . By employing BrCH2CH(OEt)2 and several other alkyl halides in the alkylation step, the corresponding S-esters were obtained. Different kinds of dithiocarbamates have been prepared by a simple, one-pot procedure from primary or secondary amines, CS2, and a variety of alkyl halides in the presence of anhydrous K3PO4 under mild conditions in good yields . In a number of cases, the alkylation of the dithiocarbamates, e.g., with an -halogenated ketone, was followed by cyclization to yield thiazole-2(3H)-thiones .

Functions Containing a Thiocarbonyl Group and at Least One Halogen

531

For the rapid synthesis of various thiadiazolylthiazol-2(3H)-thiones, a microwave-accelerated solid-state protocol has been described . The preparation of the thiazolidinethiones from (1R,2S)-ephedrine or (1R*,2S*)-norephedrine was found to involve inversion of the configuration, as determined by X-ray analysis . Employing different alkylating agents, further heterocycles containing the SC(S)N fragment have been synthesized: rhodamines with RCHBrCO2 and thiazole derivatives with CH2ClCO2Et . When the reaction of aromatic primary amines with CS2/Et3N was followed by treatment with aqueous hydrogen peroxide, the corresponding benzoxa(thia)zol-2-thiones were obtained .

(ii) From metal or ammonium dithiocarbamates The S-alkylation, S-arylation, or S-acylation of alkali metal or ammonium dithiocarbamates by alkyl halides and related compounds is another general synthetic method for the preparation of the S-esters of the dithiocarbamates (Scheme 31). S R2N C

S +

R'

S M

+

CH2 Cl

O R'

C

R2N C

SCH2R' S

R2N C

Cl

S C(O)R'

Scheme 31

New, substituted triazolyl dithiocarbanilates and benzofuranyl dithiocarbamates have been synthesized using this methodology. N-hydroxy thiazole-2-thione, loaded on a Wang resin, was treated along similar lines and was successfully used as a supported reagent for a solid-phase version of the photochemical generation of radicals . A polymer-supported diethyldithiocarbamate anion reacted with primary and secondary alcohols via their trifluoroacetates and produced alkylated dithiocarbamates in good yields . Treatment of a terpene alcohol with zinc N,N-dimethyldithiocarbamic acid in the presence of triphenylphosphine and DEAD proceeded with inversion of the configuration at the carbon atom to provide the dithiocarbamate in 75% yield after chromatography (Equation (32)). R

R PPh3 DEAD Zn(SC(S)NMe2)2 toluene

HO

Me2N

S

ð32Þ

S

Allyldithiocarbamates (Me2NC(S)SCH¼CHAr) have been produced by the reaction of sodium dithiocarbamate with BrCH2Ph3P+Br. The intermediate, Me2NC(S)SCH2Ph3P+Br, in the presence of t-BuOK underwent a Wittig reaction with aldehydes to form the allyl dithiocarbamates in good yields . The aryliodonium salts proved to be very useful for the synthesis of S-aryl dithiocarbamates; nucleophilic attack of sodium dithiocarbamate afforded the sodium salt, after acidification of the corresponding dithiocarbamate (Equation (33)). O H O

N N H

O

+

IPh

i. Et2NC(S)SNa

O

DMF rt ii. HCl

H O

S S C

N

NEt2 N H

O

Polymer-supported diaryliodonium salts have also been employed .

ð33Þ

532

Functions Containing a Thiocarbonyl Group and at Least One Halogen

Alkali metal dithiocarbamates also readily react with alkenes, exhibiting both electrophilic and nucleophilic properties, to form the corresponding S-alkylated reaction products (the same as they do with 1-naphthyldiazonium salts to provide the 1-naphthyl-azophenyl dithiocarbamates ).

(iii) From isothiocyanates The addition of thiols to isothiocyanates yielded the N-monosubstituted esters of dithiocarbamic acid. Triethylamine was found to accelerate the reaction. Isothiocyanates and -thiobutyrolactone, when gently heated with NaOH in a dioxane/water system and followed by acidification, yielded the 4-thiocarbamoylthiobutyric acids , which can be easily cyclized to the seven-membered 2-thioxo-1,3-thiazepan-4-ones (Equation (34)). O i. NaOH

R N C S + S

O

R

S

R

O

ð34Þ

N

N C

ii. HCl

H

S

OH

S

S

The nucleophilic addition of NaHS to hexa-2,4-dienoyl isothiocyanate afforded the cyclized 6-(propen-1-yl)-2-thioxotetrahydro-4H-1,4-thiazin-4-one (Equation (35)). O

C NCS

O

NaSH i. MeOH

NH

ð35Þ

ii. Acetone S

S

The corresponding benzothiazine-2-thione hetereocycle was prepared by intramolecular heteroconjugate addition of isocyanates promoted by the CS2/TBAF system . Similarly, starting from isothiocyanates, -D-(glucopyranosyl)-tetrahydro-2-thioxo-4H-1,3-thiazin-4-ones and thiazole-2-3H-thiones were prepared.

(iv) From thiuram disulfides Anions of enolized heteroaromatic 1,3-dicarbonyl systems reacted with tetraalkylthiuram disulfides, which in the reaction system DMF/K2CO3 were sufficiently electrophilic to produce the heterocyclic dithiocarbamates in good yields . Treatment of the doubly lithiated 2-(pivaloylamino)pyridine with tetraisopropylthiuram disulfide gave rise to the 3-diisopropyldithiocarbamato derivative in high yield (Scheme 32). OH

OH

O

(R2N-C(S)S)2

NH CO t Bu

NR2

O

i. BuLi ii. (i-Pr2NC(S)S)2 N

S S C

DMF/K2CO3

iii. HCl 73%

S C N

S Ni-Pr2

NH CO t-Bu

Scheme 32

The tetraethylthiuram disulfides also reacted under different reaction conditions with perfluoroorgano silver(I) and perfluoroorgano cadmium compounds to provide the corresponding perfluoroorgano esters of diethyldithiocarbamic acid and metal diethyldithiocarbamates MSC(S)NEt2 (M = Ag or Cd/2), the latter product precipitating immediately in THF (Equation (36)).

Functions Containing a Thiocarbonyl Group and at Least One Halogen S Et2N C

+

XRf

S 2

S

THF –30 °C

Et2N C

S

+

X S

SRf

533

C NEt2

ð36Þ

X = Ag, Cd/2

(v) Other methods Metal diethyl dithiocarbamates and their N-methyl quarternary salts have been shown to be efficient methyldithiocarbonyl transfer reagents for the syntheses of dithiocarbamates (Scheme 33). S N C SMe

N

S

R2NH

Me N

R2N C

EtOH/∆

S N C SMe

SMe

I

Scheme 33

The yields for a number of aliphatic/aromatic primary and secondary amines were high, 70–85% (except for R = t-Bu), thus providing a facile route to methyldithiocarbamates from nonhazardous starting materials. The chemistry of both tri- and pentavalent compounds of As, Sb, and Bi from xanthate- and dithiocarbamate-based ligands has been reviewed . Both arylalkylidene rhodanine and methyldithiocarbonyl transfer reagent for use in solid-phase combinatorial synthesis (Equation (37)).

O

O C

H N O

S N

S O

S S

N

ð37Þ

S

O

(vi) N-acyl-1,3-thiazolidine-2-thiones as auxiliary agents N-acyl-1,3-thiazolidine-2-thiones have been employed in auxiliary-based highly diastereoselective aldol additions. For the enolization, TiCl4/()-sparteine and TiCl4/N-ethylpyrrolidine/CH2Cl2 followed by an aldehyde were employed. Diastereoselectivities greater than 90:10 were obtained (Equation (38)). S

O N

S

TiCl4 /amine

R

N

S

OH O

S

OH O

S

+

R

N

S

ð38Þ

R CHO >50% >90:10

The influence of several Lewis acids on the stereoselectivity and overall yield has been examined ; the best diastereoselectivity was obtained when using SnCl4. The same high diastereoselectivity was achieved for the Lewis acid-mediated cross-coupling reaction of dimethylacetals (up to 98:2) .

534 6.17.2.4.3

Functions Containing a Thiocarbonyl Group and at Least One Halogen Bis-[thiocarbamoyl](thiuram)disulfides

Bis(thiocarbamoyl)disulfides were obtained by oxidation of the salts of dithiocarbamic acid (not always isolated). A wide range of oxidation reagents have been used, from chlorine to ammonium persulfate (COFGT (1995)). A new, attractive method under mild conditions has been reported for obtaining the tetraalkylthiuram disulfides (R = Me, Et, i-Pr, cyclohexyl, CH2CH2OH). Dialkyldithiocarbamic acid or the sodium salt were subjected to sodium chlorite, and the tetraalkylthiuram disulfides were obtained instantaneously, pure and in very high yields (Equation (39)). S

NaClO2/H2O

R2N C

0–5 °C, 20 min

SH

S S R2N C

C NR2

ð39Þ

S S

73–93%

Tetrabutylthiuram disulfide and bis[(3-methoxycarbonyl-5-methyl-pyrazol)-1-yl thiocarbonyl] disulfide were prepared by dissolving the appropriate amine in ethanol, adding CS2 to the cooled solution followed by the addition of solid iodine. Yields ranged from 83% to 90% .

6.17.2.5

Trithiocarbonates (Esters of Trithiocarbonic Acid)

Trithiocarbonic acid has been isolated as a reddish liquid at room temperature (m.p. –26.9
C) but is unstable and decomposes into CS2 and H2S. At 78
C though, it can be stored for extended periods of time. The salts of trithiocarbonic acid are more stable and rather easily available. With the exclusion of moisture, they can be stored without decomposition .

6.17.2.5.1

Salts of monoesters of trithiocarbonic acid

The blood-red trithiocarbonate anion S¼CS22 has been prepared by treating ammonium sulfide, strong aqueous ammonia, alkali metal sulfides, or aqueous alkali metal hydroxide with CS2 . To promote the reaction, a phase-transfer catalyst or an anion-exchange resin has often been used . The reaction of aliphatic and aromatic thiolates with polarized CS2 leads to the formation of the salts of the monoesters of trithiocarbonic acids, e.g., the stable triethylbenzylammonium (TEBA) salts of the corresponding trithiocarbonic acid (Equation (40)). +

N

6.17.2.5.2

N CH2 CN

TEBA Cl – CS2/OH

–

CN N CH N C S + – TEBA S

S CS2

S +

TEBA

ð40Þ

S +

TEBA

Diesters of trithiocarbonic acid

(i) From thiophosgene or xanthates The diesters of trithiocarbonic acid have been produced from thiophosgene and thiols, thiophenols, or their salts. The dithiols and dithiolates as well as disilanylsulfanyl derivatives produced cyclic trithiocarbonic esters. In the case of the disilanylsulfanyl derivatives, the reaction yields were shown to improve considerably if phenyl chlorothionoformate PhOC(S)Cl was used instead of thiophosgene. The 1,3-dithiol-2-thione derivatives were also obtainable as cyclization products of the RSC(S)Oi-Pr derivatives, which were synthesized from pyridyl acyl bromide and NaSC(S)Oi-Pr (Scheme 34).

Functions Containing a Thiocarbonyl Group and at Least One Halogen N

C

P4S10

S O

CO CH2 S C

N

H2O 45% N

N

C

70 °C

Oi-Pr

S

70%

S

H2SO4, 50 °C

S

NaSC(S)Oi-Pr

COCH2Br

535

S S

Scheme 34

(ii) From carbon disulfide Symmetrical trithiocarbonates were obtained directly and in excellent yields by the reaction of primary or secondary alkyl, benzyl, or allyl halides with KOH and CS2 in anhydrous THF (Equations (41) and (42)). S 2 RX

CS2, KOH, THF

R S

S R

ð41Þ

60–90% X = Hal Me

Me NC HS

CN N Ph

CS2/ TEA, Pb(ac)2

NC O

O

Me CN NC S

N Ph

S

S

CN

ð42Þ N Ph

O

The corresponding bis(azinyl)trithiocarbonates were synthesized from the corresponding pyridone thiol using the same methodology but by using CS2 in the presence of triethylamine and Pb(II)Ac2 . In the presence of an anion-exchange resin in the hydroxy form, primary, secondary, allylic, and benzylic halides were converted, by the reaction with CS2 under mild reaction conditions, exclusively into the corresponding dialkyl trithiocarbonates. They were obtained as virtually pure products (according to 1 H NMR) in excellent yields (>90%) and in considerably shorter reaction times . The synthesis of the 1,3-dithiol-2-thione-4,5-dithiolate anion employing the carbon disulfide route (CS2/Na/DMF) has been reviewed in 1995 . A convenient, one-pot preparation of 1,3-dithiol-2-thiones and 1,3-diselenol-2-selenones, substituted with phenyl, alkyl, alkylthio, hydroxymethyl, or formyl groups, from readily available acetylenes and CS2 has been reported in good-to-excellent yields (Equation (43)). i. n-BuLi/ THF ii. X R C CH

iii. CX2

X

R

X

H

X

ð43Þ

>75% X = S, Se; R = H, Ph, SMe, n-Hex, CH(OEt)2

Tetramethylethylenediamine was usually found to be effective for enhancing the yields, especially for the selenium compounds.

(iii) From the salts of trithiocarbonic acid or monoesters Vinyl esters of trithiocarbonic acids have been stereoselectively prepared by the reaction of potassium S-alkyl(aryl) trithiocarbonates with vinyl(phenyl)iodonium tetrafluoroborate (Equation (44)).

536

Functions Containing a Thiocarbonyl Group and at Least One Halogen S S R'CH CHI

+

RS C

+

THF

– PhBF4

R' CH CH S

rt >60%

SK

SR

ð44Þ

R = Et, PhCH2, Ph; R' = Ph, n-Bu

In the case of R1 = Ph, retention of the configuration was observed. However, in the case of R1 = n-Bu, complete inversion of the configuration was obtained, the reaction probably proceeding via an SN2-type reaction mechanism.

(iv) From bisalkoxythiocarbonyl disulfides The 1,3-dithiol-2-thione ring was also prepared in a one-pot reaction from bis(diisopropyloxythiocarbonyl) disulfide and various alkynes under radical conditions, the five-membered heterocycle being formed via the ring closure of a vinyl radical (Equation (45)). R

(i-PrS-C(S)-S)2

R'

S

S

AIBN >40%

S

R

ð45Þ

R'

R, R' = aryl, alkyl

The reaction was optimal for alkynes conjugated with a C¼C double bond.

(v) Other methods The reaction of stannylenes with an excess of CS2 resulted in the formation of a chrome-yellow asymmetric alkene, the structure of which was established by X-ray diffraction (Scheme 35). S

Tbt

i. CS 2(5 equiv.)

Sn : Tip

Tbt Sn

–70 °C

S

S

Tip

C C S

S S Sn Tbt Tip

R R

R = CH(SiMe3)2(Tbt) i-Pr(Tip)

R

Scheme 35

The strain inherent in the thietene ring serves as the driving force for its expansion via breakage of the weak CS bond under mild conditions. The ring expansion using CS2/THF was catalyzed by alkali metal halides and afforded the corresponding six-membered dithiocarbonates in high yields . The products were obtained as racemates (Equation (46)). Ar S

S

N S

CS2/ THF Ar

rt

Ar S

S

N

S S

S

ð46Þ

Ar

Two types of naphtho-fused 1,3-dithiol-2-thiones have been synthesized by the reaction of 3,4,7,8-tetrachloronaphtho[1,8-cd:5,6-c0 d0 ]bis(1,2-dithiol) with sodium trithiocarbonate (Equation (47)).

537

Functions Containing a Thiocarbonyl Group and at Least One Halogen S S Cl

Cl

Cl

Cl S

S

SR

S i. Na2S2C S ii. R–X

Cl

S

S

Cl S

S

ð47Þ

SR

S R = alkyl, benzyl

(vi) The organic chemistry of 1,3-dithiol-2-thione 1,3-Dithiol-2-thione, after lithiation with LDA, reacted with aryl carbaldehydes to afford the bisalcohol products in excellent yields. (Equation (48)). Ar S

LDA Aryl–CHO

S S

S

OH OH

S S

ð48Þ

Ar

The diols were observed to slowly decompose at ambient temperature. Dihydro-1,3-dithiol-2-thione was converted into a polycyclic sulfonium salt by reaction with acetylenes or benzyne (generated by the thermolysis of 2 equiv. of 2-carboxybenzenediazonium chloride) (Equation (49)). COOMe

S S

S DMAD

+

MeOOC

S

–

S

S COOMe

ð49Þ

+

MeOOC

COOMe

COOMe

In the first case, the short-lived ylide was trapped; in the second case, the sulfonium salt was isolated in good yield and was utilized as the starting material for the synthesis of a number of macrocylic rings of various ring size. Direct cycloaddition of C60 to a diene, formed in situ by the thermal extrusion of SO2 from the corresponding 1,3-dithiol-2-thione derivative, yielded the cycloadduct in 61% yield (Equation (50)). C60

S +

O2S

S S

Chlorobenzene ∆

S C60

S

ð50Þ

S

The C60 adduct was obtained as an inclusion compound of CS2, the application of heat under high vacuum gave the solvent-free thione.

(vii) Synthesis and chemistry of 1,3-dithiol-2-thione-4,5-dithiolates and their zinc complexes 1,3-Dithiol-2-thione-4,5-dithiolates, their zinc complexes, and other derivatives are useful starting materials for the preparation of -donor molecules, precursors of organic conductors, and superconductors. Methods for their preparation prior to 1995 have been reviewed . An alternative method for the preparation of 1,3-dithiol-2-thione-4,5-dithiolate, the zinc complex, and 4,5-ethylenedithio-1,3-dithiol-2-thione has been published (Scheme 36). In the presence of a dienophile, the latter undergoes Diels–Alder-type pericyclic reactions . 4,5-Ethylenedithio-1,3-dithiol-2-thione was readily alkylated using 2-chloroethanol [or 3-bromopropanols, 2-(2-chloroethoxy)ethanol, etc.]

538

Functions Containing a Thiocarbonyl Group and at Least One Halogen

CS2

Na/DMF 0 °C 95–100%

NaS

S

H+

S

R1

S

S

R2

S

S

S +

S NaS

R1

S

S

S

S

S R2

Zn eO ,M 2 Cl Br N 4 Bu H S

S

S

S

S

(Bu4N)2 Zn

2

Scheme 36

, benzoyl chloride , or 2-chloro-2-phenylacetophenone to form symmetric, dialkylation products. The monoalkylated product 4-alkylthio-1,3-dithiol2-thione was obtained from the zinc complex of 1,3-dithiol-2-thione-4,5-dithiolate using electrophilic reagents in the presence of 3-picolylchloride hydrochloride or 4-picolyl chloride hydrochloride or pyridine hydrochloride . The treatment of the 4,5-diphenacyl-1,3-dithiol-2-thiones obtained in this manner with Lawsson’s reagent in refluxing toluene led to the formation of six-membered heterocycles when R was Ph or 4-NO2Ph, and to the fused thiophene derivative when R was 4-MeOPh . Similarly, the condensation of dicesium 2-thioxo-1,3-thiol-4,5-diselenolate with bisalkylating polythioethers in high dilution leads to a number of thiaselena crown compounds . The neutral 1,3-dithiol-2-thione-4,5-dithiolate complexes with organic antimony and ruthenium (NO, cyclopentendienyl) , ruthenium (¼O) , dinuclear bis[dicarbonyl(cyclopentadienyl)]diiron(II) , cadmium , and palladium complexes , have been synthesized and characterized by X-ray diffraction.

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540 1997CL389 1997H2471 1997IC1890 1997JA7883 1997JCS(P1)2019 1997JOC1668 1997JOC4159 1997JOC8309 1997LA757 1997M881 1997MIP5621132

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Ravinder, P. Krishnaiah, Y. Venkateswarlu, Synlett 2001, 625–626. S. Kim, C. J. Lim, S.-E. Song, H.-Y. Kang, Synlett 2001, 688–690. P. Csomos, G. Bernath, P. Sohar, A. Csampai, N. De Kimpe, F. Fu¨lo¨p, Tetrahedron 2001, 57, 3175–3183. Y. Kuwatani, T. Yoshida, A. Kusaka, M. Oda, K. Hara, M. Yoshida, H. Matsuyama, M. Iyoda, Tetrahedron 2001, 57, 3567–3576. Y. Gareau, M. Tremblay, D. Gauvreau, H. Juteau, Tetrahedron 2001, 57, 5739–5750. J.-C. Blazejewski, P. Diter, T. Warchol, C. Wakselman, Tetrahedron Lett. 2001, 42, 859–861. O. P.-T. Levi, J. Y. Becker, A. Ellern, V. Khodorkovsky, Tetrahedron Lett. 2001, 42, 1571–1573. R. N. Salvatore, S. Sahab, K. W. Jung, Tetrahedron Lett. 2001, 42, 2055–2058. J. Girniene, D. Gueyrard, A. Tatibouet, A. Sackus, P. Rollin, Tetrahedron Lett. 2001, 42, 2977–2980. A. Cosp, P. Romea, F. Urpi, J. Vilarassa, Tetrahedron Lett. 2001, 42, 4629–4632. T. K. Chakraborty, S. Ghosh, S. Dutta, Tetrahedron Lett. 2001, 42, 5085–5088. I. Maya, O. Lopez, J. G. Fernandez-Bolonos, I. Robina, J. Fuentes, Tetrahedron Lett. 2001, 42, 5413–5416.

2000T5413 2000T5819 2000T7173 2000TL4895 2000TL5729 2000TL5833 2000TL9815 2000ZN231 2001BMCL1609 2001CAR123 2001CC369 2001CC2618 2001CHE1424 2001CL103 2001CPB361 2001EJI1625 2001H279 2001H301 2001IC2570 2001JA4717 2001JA5602 2001JIC372 2001JOC894 2001JOC1061 2001JOC2104 2001JOC3940 2001JOC8935 2001L5621 2001MI232 2001MI234 2001MI269 2001MI365 2001MI372 2001MI749 2001OL615 2001OL855 2001OL1069 2001OL1941 2001OL2141 2001S1965 2001SC817 2001SL625 2001SL688 2001T3175 2001T3567 2001T5739 2001TL859 2001TL1571 2001TL2055 2001TL2977 2001TL4629 2001TL5085 2001TL5413

Functions Containing a Thiocarbonyl Group and at Least One Halogen 2001TL7091 2001TL8625 2001ZAAC1264 2002CAR397 2002CEJ1856 2002CL1879 2002HAC280 2002ICA71 2002IJC1234 2002IJC(B)1510 2002JCS(D)1377 2002JOC6896 2002JOM94 2002MI13 2002OL2253 2002T2339 2002T2831 2002TA759 2002TL2801 2003CCR35 2003JPC(A)4697

543

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544

Functions Containing a Thiocarbonyl Group and at Least One Halogen Biographical sketch

Professor Erich Kleinpeter obtained his diploma from the University of Leipzig, Germany in 1970 and his Dr. rer. nat. in 1974 under the direction of Professor Rolf Borsdorf. He continued teaching and research work at the University of Leipzig until 1979, when he spent a year in the laboratories of Professor Rainer Radeglia at the Academy of Sciences, Berlin. Following this, he returned to Leipzig and habilitated in 1981. After spending 1982–1985 as Associate Professor of Organic Chemistry at the University of Addis Ababa, Ethiopia, he moved to the University of Halle-Wittenberg, Germany, where he was appointed a docent in spectroscopy, followed later by his appointment as Professor of Analytical Chemistry in 1988. In 1993 he took up his present position as full Professor of Analytical Chemistry at the University of Potsdam, Germany. His research interests include all aspects of physical organic chemistry, in particular the application of NMR spectroscopy, quantum chemical calculations, and mass spectrometry to the examination and investigation of all kinds of interesting structures and new phenomena in organic, bioorganic, and coordination chemistry.

# 2005, Elsevier Ltd. All Rights Reserved No part of this publication may be reproduced, stored in any retrieval system or transmitted in any form or by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers

Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 495–544

6.18 Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms Other Than a Halogen or Chalcogen J. BARLUENGA, E. RUBIO, and M. TOMA´S Universidad de Oviedo, Oviedo, Spain 6.18.1 THIOCARBONYL DERIVATIVES CONTAINING AT LEAST ONE NITROGEN FUNCTION (AND NO HALOGEN OR CHALCOGEN FUNCTIONS) 6.18.1.1 Thiocarbonyl Derivatives with Two Nitrogen Functions 6.18.1.1.1 From isothiocyanates 6.18.1.1.2 From carbon disulfide 6.18.1.1.3 From thiophosgene 6.18.1.1.4 From thiocarbonyl transfer reagents 6.18.1.1.5 From ureas 6.18.1.1.6 Miscellaneous methods 6.18.1.1.7 From thiocyanate salts and alkyl thiocyanates 6.18.1.1.8 From thiocarbamoyl transfer reagents 6.18.1.1.9 From sulfur-transfer reagents 6.18.1.2 Thiocarbonyl Derivatives with One Nitrogen and One Phosphorus Function 6.18.1.2.1 From isothiocyanates 6.18.1.2.2 From halothioamides 6.18.1.2.3 From thiophosphinoyldithioformates 6.18.1.2.4 From phosphonodithioformates 6.18.1.2.5 Miscellaneous methods 6.18.2 FUNCTIONS CONTAINING AT LEAST ONE METALLOID FUNCTION 6.18.2.1 Thiocarbonyl Derivatives with Two Silicon Functions 6.18.2.2 Thiocarbonyl Derivatives with Two Phosphorus Functions

6.18.1

545 545 545 553 555 555 556 556 557 559 561 564 564 566 567 567 567 568 568 568

THIOCARBONYL DERIVATIVES CONTAINING AT LEAST ONE NITROGEN FUNCTION (AND NO HALOGEN OR CHALCOGEN FUNCTIONS)

6.18.1.1 6.18.1.1.1

Thiocarbonyl Derivatives with Two Nitrogen Functions From isothiocyanates

The addition reaction of amines to isothiocyanates still continues to be the most general access to a wide array of thiourea derivatives (Equation (1)). In this section, some recent results concerning new improvements as well as the application in the synthesis of molecules of interest are highlighted. 545

546

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms R1 N C S

H N

+ R2

S R3

35–100%

R1HN

NR2R3

ð1Þ

R1

= alkyl, aryl R2, R3 = H, alkyl, aryl

Recently, Fuentes and co-workers have reported the synthesis of thioureylene di-C-nucleosides, a new type of dinucleotide analog, based on the addition of amines to isothiocyanates (Scheme 1). Thus, the reaction of 30 -amino-C-nucleosides with 30 -isothiocyanatoC-nucleosides, which are in turn formed by reaction of the corresponding amine nucleosides with thiocarbonyldiimidazole (TCDI), produces thioureylene di-C-nucleosides in very high to quantitative yields. S NH2

R1

O

SCN

R2

O

+ OAc

OAc

DMF or acetone

HN

NH

R1

40 °C 80–100%

O

O

R2

OAc

OAc

R1, R2 = furan, imidazoline-2-thione, pyrrole derivatives

Scheme 1

In a study focused on nonbiarylatropoisomers derived from carbohydrates, Palacios and co-workers have described a facile access to chiral cyclic thioureas, specifically 2-aryl-5-hydroxyimidazolidine-2-thiones, in moderate yields via addition of D-glucosamine to aryl isothiocyanates (aryl = 2-FC6H4, 2-ClC6H4, 2-BrC6H4) (Scheme 2). A related reaction involving D-fructosamines with different sugar isothiocyanates has been released .

S OH

HO HO

EtOH–H2O

O

+

ArN=C=S 45 °C 65–76%

OH NH2

Ar N HO HO

NH H OH OH CH2OH

Ar = 2-X-C6H4; X = F, Cl, Br

Scheme 2

A high-yielding synthesis of guanidium derivatives from ethyl carbamate protected thioureas was reported. The latter were in turn prepared by addition of amines to ethyl thiocyanato formate . Some modern techniques have been incorporated for the synthesis of the thiourea functional group in order to overcome inherent difficulties found in the traditional methods. For instance, fluorous electrophilic scavengers for solution-phase synthesis have been successfully tested (Scheme 3) . Thus, fluorous isatoic anhydride 1 and isocyanate 2 are used as scavengers for amines in solution-phase synthesis of thioureas from isothiocyanates and excess of primary and secondary amines. The fluorous derivatives thus formed are readily separated from the reaction mixture by solid-phase extraction (SPE) over fluorous silica. The yields are in general high, particularly with the fluorous scavenger 1, and the purity greater than 95% after the scavenging operation.

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms S

i. R1R2NH (1.5 equiv.)/CH2Cl2 PhNCS ii. 1 or 2 (1.0 equiv.)/SPE

72–100% (from 1) NR1R2

PhHN

547

1 = alkyl,

R

34–98% (from 2)

H

R2 = alkyl C8F17

N O

O

C8F17

O 1

NCO 2

Scheme 3

In addition, solid-state reactions have also become promising in the thiourea system synthesis. Thus, Kaupp and co-workers have reported a series of solid-state reactions between solid or gaseous amines and solid isothiocyanates to produce substituted thioureas in quantitative yields (100% yield, 53 examples) (Scheme 4). Except for washing in a few cases, the reaction does not require work-up, and allows for upscaling to the kilogram scale. S

R2R3NH R1NCS

R1HN

–30 °C to rt

NR2R3

R1 = Ar, Me R2 = Ar, Me, H R3 = Me, H

solid state 100 %

Scheme 4

The high-pressure technique has been applied in the preparation of a number of thioureas derived from aryl- and cyclohexyl-substituted isothiocyanates and different amino-substituted pyridines and diazines (Scheme 5) . The yield of the high-pressure reaction is significantly higher (67%) than that of the thermal reaction (29% along with 38% of N,N0 -diphenylthiourea) as it was found for the model components 4-aminopyridine and phenyl isothiocyanate. H N

NH2 +

N

PhNCS S

N

THF, reflux

NHPh

THF, 40 °C, 0.6 GPa

29% 67%

NH2 N H 2N

N

H2N

N

NH2

N

N

N

N NH2

N

NH2

THF, 40–80 °C 0.6 GPa 47–95%

4-MeO-C6H4-NCS

4-Me2N-C6H4-N=N

NCS

c-C6H11-NCS

Scheme 5

Cyclic thioureas, particularly thiohydantoins, have attracted much attention mostly because of their biological properties. A practical eco-friendly procedure for the synthesis of 2-thiohydantoins and 5-alkylamino-2-thiohydantoins has been developed recently using the solvent-less

548

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

technique (Scheme 6) . Thus, the reaction of methylglycinate hydrochloride with isothiocyanates in refluxing diethyl ether or ethyl acetate gives rise to simple 2-thioxoimidazolidin-4-ones, which are in turn transformed into 5-aminomethylidene derivatives by treatment with dimethylformamide diethylacetal (DMF-DEA) under solventless microwave irradiation. Cl–

TEA

+

H3N

CO2Me

S

Et2O or EtOAc

+ reflux

R-NCS

R

H N

DMF–DEA no solvent

S

O

Microwave 70–80 °C

R

N

~96%

R = Me, Bu, Ph

H N

N

N O

74–77%

Scheme 6

Following this report, Dannhardt and co-workers have investigated the affinity to the glycine site of the NMDA receptor of different indole-2-carboxylic acids having a thiohydantoinmethyl substituent at C-3. The preparation of the target molecules involves reductive amination of ethyl 3-formylindole-2-carboxylate with various amino acid esters followed by cyclization with isothiocyanates and ester hydrolysis (Scheme 7) . i. H2NCHR1CO2Me

Cl

ii. R2NCS Et3N/∆

CHO

N

Cl

iii. LiOH

N H

O R1

CO2Et Cl

R2 N

S

Na(AcO)3BH

CO2H

N H

Cl

R1 = H, Me, Pri R2 = Et, aryl

Scheme 7

In the course of studies directed to the total synthesis of batzelladine alkaloids, Elliot and co-workers have reported a short access to substituted pyrrolo[1,2-c]pyrimidine-1-thiones (Scheme 8) . First, the necessary alkenyl pyrrolidine substrate is obtained from glutamic acid in five steps. Then, the key annulation step is based on the previous report by Kishi and is accomplished by the three-component reaction of alkenyl pyrrolidine, silicon tetraisothiocyanate, and acetaldehyde at room temperature. Si(NCS)4 benzene CH3CHO

TBSO NH2 HO2C

NH CO2H

CO2Et

rt

S

TBSO N

S

TBSO NH

+

Me CO2Et 54%

N

NH Me CO2Et 27%

Batzelladine A

Scheme 8

The group of Ortiz Mellet and Garcı´ a Ferna´ndez have elegantly effected the preparation of cyclooligosaccharide receptors of different ring size featuring a hydrophobic cavity. The macrocyclic ring is constructed by double—inter and intramolecular—amine-to-isothiocyanate addition

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

549

(Scheme 9) . Thus, the cyclodimerization of diisothiocyanate and diamino disaccharides can be effected in moderate yield by mild heating in pyridine. The cyclotrimerization product is obtained from the acyclic thiourea dimer containing two isothiocyanate moieties, which is directly available by homocoupling of the corresponding diisothiocyanate disaccharide (vide infra, Scheme 14). Thus, the addition of the diamine disaccharide to the diisothiocyanate substrate affords moderate to high yields of the final cyclic pseudohexasaccharide. SCN

NCS

Pyridine

+ H2N

40 °C

NH2

HN

NH

HN

NH

S

S

40% S H

Pyridine HN

NCS

HN

NCS

H2N

S

H N

N

NH2 40 °C 25–70%

43%

N H

H N S

N H

N H

S

O RO OR =

OR RO

OR

R = OAc, TMS, H

OR

Scheme 9

The preparation of thiourea-functionalized resorcinarene cavitands, a novel class of neutral anion receptors, is also feasible starting from either isothiocyanate- or amine-containing cavitands (Scheme 10) . Thus, the reaction of the tetrakis[aminomethyl]cavitands with alkyl and aryl isothiocyanates R2-NCS allows one to isolate the corresponding tetrakis[thioureamethyl]cavitands in 27–63% yield. Conversely, a new cavitand is obtained in two steps and moderate overall yield by conversion of the aminocavitand into the isothiocyanate derivative followed by addition of the primary amine R3-NH2. The use of macrocyclic thioureas as efficient anion receptors has been extended to a variety of cyclophane-based structures. In this sense, different types of systems such as ortho–meta, meta– meta, and meta–para cyclophanes have been synthesized (Scheme 11) . The required starting materials are the 1,3-[bis(aminomethyl)]-4-,6-di-t-butylbenzene and the corresponding o-, m-, and p-bis(isothiocyanatomethyl)benzenes. The macrocyclization takes place in low-to-high yields by heating at 60
C in chloroform under high dilution conditions. Other examples using thiourea receptors with a rigid xanthene spacer have been reported . In addition, a series of fluorescent naphthylthioureas containing hydroxymethyl groups have been synthesized from naphthyl isothiocyanates and
-hydroxyamines . A new macrocyclic system containing oligoethyleneglycol chain and thiourea moieties has been prepared and their binding ability toward dihydrogenphosphate anion and several cations investigated (Scheme 12) . The synthesis of the target molecule involves the reaction of the tetraazathiapentalene derivative, prepared from the bis(pyrimidine-2-thione) and methyl isothiocyanate, with the corresponding diisothiocyanate followed by heating with base. A number of thiourea-based compounds have been found to display an array of biological properties. Since thioureas are known to raise the HDL cholesterol, some functionalized systems with a thiourea moiety embedded in a functionalized side chain, for instance those having a
-carboxylic acid group, have been prepared (Scheme 13) . Thus, the addition of acyclic N,N-bis(trimethylsilyl)-
-amino acid esters or cyclic
-amino acid esters to aromatic isothiocyanates in methanol provides the corresponding N-thiocarbamoyl-
-amino acid esters in moderate-to-high yields.

550

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

NH2 O

CH2Cl2/CHCl3/THF

O

S

H N

R2NCS

NHR2

O

O

rt to reflux 27–63% C5H11

4

C5H11 R2 = aryl,

54%

Cl2CS

H N

R3NH2

NCS

CH2Cl2 O

O

O

4

t-octyl

S NHR3 O

rt to reflux 55% C5H11

C5H11

4

4

NO2 O 4

R3 =

Scheme 10

S t-Bu

t-Bu

S

N H

N H

H N

H N

t-Bu OBu OBu t-Bu

S

N H

N H

OBu

H N

H N

OBu

t-Bu

t-Bu

S 70%

79%

CHCl3, high dilution, 60 °C

S

t-Bu

OBu

OBu

OBu or

or

OBu SCN

H N

OBu

SCN

OBu

NH2

H N

SCN

and t-Bu

N H

S 31%

SCN

NH2

N H

BuO SCN

OBu

NCS

Scheme 11

Additional examples of biologically active thioureas derived from isoquinolines, pyrrolidines, and aryl ethylamines have been reported recently. Among them, thioureas with antispasmodic activity as well as thioureas with antagonist effect on a vanilloid receptor are worth noting . On the other hand, isothiocyanates can be readily transformed into the corresponding symmetric N,N0 -disubstituted thioureas upon treatment with pyridine water. The reaction is very well suited for those cases where the required amines are not accessible. The amine-free mechanism very likely involves thiocarbamic anhydrides as reactive intermediates (Scheme 14) . This practical procedure has been applied by the authors not only to the synthesis of simple and carbohydrate-derived thioisocyanates, but also to more complex systems like cyclotetrahalins via macrocyclization of the corresponding oligosaccharide isothiocyanates (Scheme 14) .

551

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms Me N

S N

S

Me N

S

But

i, ii

S

N

N

Me N

But

N Me

N S

S

i. 3,6,9-Trioxaundecane-1,11-diisothiocyanate benzene, reflux, 56% ii. aq., KOH, EtOH, reflux, 69%

S

HN

O

HN O

=

HN O

HN

S

Scheme 12 ArNCS MeOH

CO2Et

(Me3Si)2N

R N H

N H

rt 44–95%

R

R

S Ar

R

CO2Et

R = Me R,R = –(CH2)3,5– Ar = 2X-5Y-C6H3 (X = Me, MeO; Y = Me, Cl) ArNCS CH2Cl2

HN

S Ar

CO2Et

N H

rt 77%

N

CO2Et

Ar = 2-Me-5-Cl-C6H3

Scheme 13 Pyridine/H2O (10:1) RNCS

S R

rt to 60 °C 72–95%

N H

N H

H 2O

–O C S RNCS

S R

SCN

NCS

R

R N H

H N

OH

Pyridine/H2O (15:1) 40 °C

S

HN

NCS

S HN

H N

O

NCS

R

S

Pyridine/H2O (10:1) 60 °C 38% overall

=

O RO

OR

O RO OR O OR OR

Scheme 14

HN

NH

HN

NH

S

S

552

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

During the last years some attention has been paid to the solid-phase synthesis of thioureas. For instance, the traceless synthesis of thioureas reported by Sim begins with the amination of the bromo-Wang resin followed by the addition of isothiocyanates. The thiourea unit was liberated from the resulting resin-bound thiourea by treatment with 50% TFA in CH2Cl2 (Scheme 15) . While the overall yields are high, the observed purity is rather low (13–51%). An analogous synthesis of isoxazoline thioureas using the chloro-Wang resin is also known .

S R1NH2

Br

R2NCS

NH R1

CH2Cl2 rt

N R1

CH2Cl2 rt

N H

R2

S TFA-CH2Cl2 (1:1)

R1

N H

rt

N H

R1 = Prn

R2

R2 = aryl

68–92%

Scheme 15

Thiohydantoins are in turn available by solid-phase synthesis via polymer-supported amines as depicted in Scheme 16. Thus, the sodium polystyrylsulfinate reacts with 2-choloroethanol to give a polystyrylethanol resin which is coupled with protected glycine to afford, after deprotection, the corresponding resin-bound -amino acid. The latter is added to phenyl isothiocyanate and the resulting thiourea subjected to basic or acid treatment to provide acyclic and cyclic thioureas, respectively .

i. Cl SO2Na

OH

Bu4NI

S O2

ii. BOC-gly DCC iii. HCl

O

S 4 N NaOH dioxane

PhNCS DMF 90 °C

S S O2

NH2 O

O O

N H

HO2C

N H

N H

Ph

21% overall N H

Ph O 6 N HCl dioxane 20% overall

Ph N S N H

Scheme 16

Using a similar strategy, a high-yielding microwave-assisted synthesis of substituted thiohydantoins has been accomplished. In this process, Fmoc-protected -amino acids were coupled with HO-PEG-OH, deprotected, and reacted with isothiocyanates. After base-mediated cyclization, the thiohydantoin system was liberated from the matrix under microwave exposure . The preparation of substituted isoxazolethiohydantoins has also been reported from hydroxypropyloxymethylpolystyrene, alkynyl glycine, and isothiocyanates . Moreover, it has been released an efficient solid-phase synthesis of quinazoline-2-thioxo-4-ones using SynPhaseTM lanterns supports .

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

553

The solid-phase addition of triazenes to isothiocyanates has been designed as an efficient route to a new type of thioureas, which have been further elaborated into guanidines. The starting polymer-bound triazenes are prepared by addition of primary amines to the T2* diazonium resin .

6.18.1.1.2

From carbon disulfide

The dithiocarbamic acid unit represents a suitable thiocarbamoyl transfer agent (see Section 6.18.1.1.8). In most cases they are not commercially available and must be prepared. In this way, Tomkinson and co-workers have reported a simple, high-yielding procedure for the synthesis of thioureas in two steps from carbon disulfide, via amination of dithiocarbamic acids (Scheme 17). Thus, the reaction of primary or secondary aliphatic amines with carbon disulfide results in the formation of the corresponding dithiocarbamic acids, which then undergo amination upon treatment with primary or secondary 2,4-dinitrobenzenesulfonamides. This method thus provides access to symmetrical and unsymmetrical di-, tri-, and tetrasubstituted thioureas.

CS2 pyridine R1R2NH

CH2Cl2

R3R4NSO2Ar Cs2CO3 DMF, 80 °C

S R1R2N

SH

S R1R2N

–SO2 65–76%

NR3R4

R1 = Me, H (Ar = 2,4-dinitrophenyl)

R2 = Me, Bn, Ph R3 = 4-MeOC6H4-CH2 R4 = MeOCH2CH2, H

Scheme 17

Very recently, an efficient synthesis of unsymmetrical diaminocarbene ligands via reduction of unsymmetrical imidazolidine-2-thiones has been reported . The methodology for the preparation of that type of cyclic thiourea was developed by Albrecht in 1994 by using lithium N-butyl-N-lithiomethyldithiocarbamates, readily available from N-methyl butylamine and carbon disulfide. The process consists of addition of the C-nucleophilic center of the dithiocarbamate to the imine followed by cyclization (Scheme 18) . R2

BuNHMe

i. BuLi ii. CS2 iii. BusLi

Bu S

S

NR1 N

Li SLi

R3 –78 to –10 °C 50–69%

Bu N

1 N R 2 R R3

R1 = H, Me, Pri, But R2 = H, Me, Et, Ph R3 = H, Me, Et, Pr, But, Ph R2, R3 = –(CH2)4, 5–

Scheme 18

The solid-phase synthesis has been accomplished by Mioskowski and co-workers by using a resin-bound dithiocarbamate moiety (Scheme 19). Thus, the treatment of the Merrifield resin with a primary amine in the presence of carbon disulfide produces the supported dithiocarbamate. Heating this dithiocarbamate in the presence of a

554

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

primary or secondary amine leads to the formation of the thiourea with the release of benzylthiol bound to resin. This method gives access to N,N0 -di- and trisubstituted thioureas in good yields and with 90% of purity in most cases. Cl

+ R1NH2

CS2 EtiPr2N

R2R3NH

NHR1

S

S + NR2R3

R1NH

Toluene 60 °C 33–97%

S

SH

R1 = alkyl, cycloalkyl, benzyl R2 = H, Me R3 = alkyl, benzyl R2, R3 = –(CH2)5–

Scheme 19

The synthesis of thioureas, as ‘‘en route’’ synthesis of modified chiral guanidines, has also been achieved by means of carbon disulfide itself as the thiocarbonyl source. Thus, Ishikawa and co-workers have obtained a number of unsymmetrical thioureas resulting from sequential amination of CS2 with a primary amine—via the corresponding isothiocyanate—and an enantiopure diamine (Scheme 20). Application of this strategy to the synthesis of thioureido cyclodextrins by Ph3Pmediated coupling of CS2 (‘‘phosphinimine’’ approach) with cyclodextrin amines and primary amines has been executed by Marsuda and co-workers . i. R1NH2, Et3N CH2Cl2, rt CS2

R1HN

R2 ii.

R2

S N H

NH2 R2

NH2

H2N R2 CH2Cl2, rt 54–86%

R1 = alkyl, benzyl R2–R2 = Ph, Ph (S,S); (CH2)4 (R,R); (CH2)4 (S,S)

Scheme 20

Recently, the Italian group of Sartori, Ballini, and Maggi has carried out the carbon disulfidemediated synthesis of thioureas in the presence of heterogeneous and reusable catalysts. They have found that catalysts, such as Zn–Al HT(500) (a ZnO/Al2O3 composite) and MCM-41-TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene bound to mesoporous silica), are easily prepared and behave efficiently in the synthesis of acyclic and cyclic symmetrical thioureas (Scheme 21) . RNH2 S RHN

90–100 °C NHR

cat.

NH2

H2N CS2

R = alkyl, benzyl, aryl Cat. = Zn-Al, HT (500) (100 °C, 57–100%) MCM-41-TBD (90 °C, 57–91%)

Scheme 21

90–100 °C cat.

S H N

N H

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms 6.18.1.1.3

555

From thiophosgene

Another traditional methodology based on thiophosgene is still being used. Thus, cyclic, optically active thioureas have been prepared and utilized as chiral guanidine precursors. In this way, the synthesis of 1,3-bis(phenylethyl)imidazoline-2-thione with C2-symmetry and bicyclic proline derived thiourea is shown in Scheme 22 . Examples of application of this procedure to monosubstituted thioureas is reported in the synthesis of conformationally restricted L-arginine and L-homoarginine derivatives .

CH3 Ph

H N

N H

N H

CH2Cl2, Et3N

CH3

H N O

CH3 S

CSCl2

Ph

Ph

N

CH3 N

Ph

rt, 84%

i. LiAlH4 THF, 60 °C

Ph

CH3 N

ii. CSCl2, Et3N

CH3

N Ph S

CH2Cl2, rt 47%

Scheme 22

6.18.1.1.4

From thiocarbonyl transfer reagents

The double amination of appropriately designed thiocarbonyl synthons is currently another useful synthetic route for building up the thiourea functionality. In this sense, 1-(methyldithiocarbonyl) imidazole 3 and its N-methyl quaternary salt 4 have become efficient thiocarbonyl transfer reagents for the synthesis of a diversity of thioureas (Scheme 23) . Thus, symmetrical disubstituted thioureas are formed by refluxing an ethanol solution of either transfer reagent 3 or 4 with primary amines in a molar ratio of 1:2; moreover, the use of diamines, e.g., 1,2-diaminobenzene and ethylenediamine, provides the corresponding cyclic thioureas. Unsymmetrical di- and trisubstituted thioureas are accessible in very high yields by the sequential treatment of either dithiocarbonyl derivative 3 or 4 with 1 equiv. of a primary amine and 1 equiv. of a primary or secondary amine, respectively, in refluxing ethanol.

S N

N

S + H3C N

SCH3 3

N

–

SCH3 I

4

S 3 or 4

RNH2 (2 equiv.) EtOH/∆

NHR

RHN

R2 = H, Me, aryl, c-C6H11

i. R1NH2 (1 equiv.) 3 or 4

R3 = H, Me

S

EtOH/∆ ii. R2R3NH (1 equiv.) EtOH/∆

R = aryl, alkyl R1 = Ph, benzyl, H

40–96%

R1HN

NR2R3

61–96%

Scheme 23

R2, R3 = –(CH2)5–, –(CH2)2–O–(CH2)2–

556

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

Alternatively, 1,1-thiocarbonyl diimidazole (TCDI) can be regarded as a very common thiocarbonyl transfer reagent to synthesize either symmetrical or unsymmetrical thioureas. Thus, various substituted N-pyridylthioureas with anti-HIV activity have been made accordingly, as illustrated in Scheme 24 . The thioureas resulting from primary amines, TCDI, and 1,2-diaminoarenes are immediate precursors of valuable 2-(alkylamino)benzimidazoles . i. TCDI acetonitrile

X N

X

ii. RCH2CH2NH2

NH2

S N

DMF, 100 °C

N H

R

N H

X = Cl, Br, CF3 R = aryl, 1-cyclohexenyl

Scheme 24

Several papers dealing with the solid-phase synthesis of thioureas by thiocarbonyl transfer from TCDI have also been published. For instance, Sun and co-workers have described the preparation of 3,4-dihydro-1H-quinazolin-2-thiones (72–97% yield; 60–89% purity) from resin-bound 2-methylaminoanilines, which in turn can be made from Rink resin in three steps (Scheme 25). In a similar way, the solid-phase syntheses of 1,3-disubstituted 2-thioxoquinazoline-4-ones from resin-bound 2-aminobenzamides- and of bis-2-imidazolidinethiones from resin-bound tripeptides have been undertaken . O N Fmoc H

N

i. TCDI, DMF, rt

N H

H2N NHR

ii. TFA, CH2Cl2, rt 72–97%

O

N H

R S

NH2 R = ArCH2, alkyl

Scheme 25

Recently, the synthesis of a novel C2-symmetric thiourea, as well as its application as ligand in palladium-catalyzed coupling reactions, has been developed. In this case, (1(R), 2(S))-N,N0 (2-methylphenyl)-1,2-diaminocyclohexane was transformed into the corresponding imidazolidine-2-thione in 95% yield by condensation with thiophosgene . Pentafluorophenyl chlorothioformate has been used as thiocarbonyl transfer agent in the solution and solid-phase synthesis of N-bromobenzyl-N0 -sulfonylthioureas (Scheme 26) . The use of the sulfonamide PbfNH2, as the key reagent to incorporate a TFA-labile guanidine protection group, greatly facilitates the solid-phase synthesis of N,N0 -substituted guanidine compounds.

6.18.1.1.5

From ureas

No relevant new work has been reported in this area since COFGT (1995) .

6.18.1.1.6

Miscellaneous methods

The transfer of both sulfur and nitrogen is also possible according to the report of Valle´e and Byrne which is summarized in Scheme 27 . They have found that the treatment of isonitriles with the dithioxo-bishydroxylamino molybdenum complex results in the formation of trisubstituted thioureas in good yields. The proposed reaction pathway is also described in Scheme 27.

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

Ar

i. ClCS-OC6F5, DIPEA CH2Cl2

NH2

S Ar

N H

ii. PbfNH2, KOtBu DMSO 70%

NHPbf

O Rink amide MBHA resin

557

S

N H

NHPbf

N H

SO2 Ar = Br

Pbf =

CH2

O

Scheme 26

S R N C + Et2N

Mo O

S

S NEt2

CHCl3

RHN

60 °C

O

NEt2

76–82% (R = Bn, c-C6H11) H2O

RN S Et2N +

–

O

RN

S

Mo

S

S

NEt2

Mo Et2N

O

O

NEt2 O

Scheme 27

6.18.1.1.7

From thiocyanate salts and alkyl thiocyanates

The thiocyanate salts represent an attractive alternative to isothiocyanates, particularly when they are difficult to prepare, as it was demonstrated in the past. Recently, the general procedure has been improved and the scope enhanced by Meckler and co-workers . In this case, high yields of primary monosubstituted or symmetrical N,N0 -disubstituted thioureas can be reached by refluxing potassium thiocyanate and amine hydrochloride in THF or xylenes, respectively (Scheme 28). This approach tolerates sterically bulky primary amines and the resulting thioureas are usually isolated by a simple filtration of the reaction mixture.

S R

N H

THF NH2

reflux 73–96%

R NH2.HCl +

S

Xylenes R reflux

KSCN

N H

N H

R

66–96%

R = alkyl, aryl, (R)-PhCH(Me)

Scheme 28

558

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

Glycopyranosylidene spirothiohydantoins have been prepared from per-O-acetylated 1-bromo1-deoxy-
-D-glycopyranosacarboxamide, which is in turn available by radical-mediated bromination of the corresponding glycopyranosyl cyanide (Scheme 29) . Heating of a nitromethane solution of the bromoamide and potassium thiocyanate in the presence of a small amount of elemental sulfur resulted in the formation of the spirothiohydantoins in good yields. According to the authors, the reaction probably initiates by a single-electron transfer (SET) from thiocyanate to the bromoamide and involves the coupling of the radicals in the solvent cage.

KSCN S8

R

O

AcO AcO

AcO

R

MeNO2 CONH2

AcO AcO

H N

AcO

80 °C

Br

O

S

O

(R = CH2OAc, H)

N H

64–79 °C

SET

Solvent cage O

SCN CONH2

Scheme 29

In a completely different approach, diastereomerically and enantiomerically pure 4-vinyltetrahydro-1H-imidazole-2-thiones are synthesized from chiral aminoallyl thiocyanates (Scheme 30) . Thus, these allyl thiocyanates, which are readily accessible from chiral aminoallylic alcohols, lead to the observed cyclic thioureas by a thermal domino reaction consisting of a [3,3]-sigmatropic rearrangement followed by stereocontrolled intramolecular amine addition to the isothiocyanate functionality.

NHBOC OMs

R

Xylene

KSCN MeCN

NHBOC R

85–90%

S

R = Me, Et, Pri, Bn, Bni N Xylene 2-hydroxypyridine (0.1 mol.%) 80 °C, 3 h 80–89%

NHBOC

80 °C 3h

R N C S

S BOC N

NH

R ≥96% de

Scheme 30

The one-pot synthesis of a series of N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thiones was carried out starting from cheap materials such as hydrazines, -bromoketones, and potassium thiocyanate and their anti-HIV and anti-SIV activity studied (Scheme 31) . The mechanism proposed by the authors is outlined in the scheme and involves the [3+2]cycloaddition of 1,2-diazadienes and isothiocyanic acid leading to an azomethine imine dipole as the key step. Finally, the [1,4]-H shift would complete the mechanistic pathway. Alternatively, 1,2,4-triazepine-3-thiones are formed by refluxing in DMF, a mixture of ,
-unsaturated ketones and hydrazinediium dithiocyanate .

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

2

+

R3

R2

S R1 HN N NH

KSCN AcOH

O R1NHNH

30 °C 32–92%

Br

559

R2

R3

–SCN

R1 HN

R1 N

N SCN

R2

R1

S

C

N

NH

R2

R3

–

S +

N N

NH H R3

R2

R3

Scheme 31

In a previous work, Schantl and Na´denı´ k reported that using disubstituted bromoketones, instead of monosubstituted ones, the azomethine imine intermediate cannot stabilize by hydrogen migration, so that a second dipolar cycloaddition to isothiocyanic acid occurs yielding efficiently hexahydro-1H-imidazo[1,5-b][1,2,4]triazole-2,5-dithiones. Overall, the initially formed 1,2-diazadiene undergoes two consecutive [3+2]-cycloaddition reactions to isothiocyanic acid in a ‘‘crisscross’’ fashion (Scheme 32) .

O

R2

R1 Br

R3

PhNHNH2 KSCN AcOH

S Ph – + N N NH R2 1 R3 R

HNCS

S

Ph N N

S

NH N R3 1 H R R2

R1 = H, R2 = R3 = Me (70%) R1 = H, R2 = Me; R3 = Ph (80%, de = 48%) R1 = Me, R2 = R3 = Me (91%)

Scheme 32

Moreover, Takahashi and Miyadai reported the ‘‘criss-cross’’ cycloaddition of 1,4-diazadienes to trimethylsilylisothiocyanates, as masked isothiocyanic acid, affording moderate yields of perhydroimidazo[4,5-d ]imidazole-2,5-dithiones (Scheme 33) . Later, Pota´cek and co-workers undertook a detailed study of the ‘‘criss-cross’’ cycloaddition of 1,4-diazadienes with mixtures of isothiocyanic acid and isocyanic acid, generated in situ from potassium salts and acetic acid (Scheme 33). Although, mixtures of 2,5-dithione and 5-thioxo-2-one derivatives were formed, they found the isothiocyanic acid to be more reactive, the mixed derivatives being best obtained by slow addition of a 2:1 mixture of cyanate/thiocyanate salts to the aldazine in acetic acid.

6.18.1.1.8

From thiocarbamoyl transfer reagents

Nitrosothioureas serve as a useful source of the thiocarbamoyl unit. Thus, the room temperature treatment of aliphatic primary and secondary amines with N-nitroso-1,3-dimethylthiourea (DMNT) leads to very high yields of N-methylthioureas. Starting with N-nitroso-1,3,3-trimethylthiourea (TMNT), the analogous N,N-dimethylthioureas are produced again in high yields (Scheme 34) .

560

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

R

N

N

Me3SiNCS THF R

R N

H N

N H

N R

S

rt 24–53%

S

R = c-C6H11, 4-MeOC6H4

R

N

N

R + KOCN

+ KSCN

AcOH

R N

H N

N H

N R

S

rt

X

1:2:1 R

X = O/X = S 84/13 96/4 76/24

c-C6H11 4-MeOC6H4 But

Scheme 33

S Me O

N N

N R1

S

R2R3NH

Me

Me

acetonitrile rt

DMNT (R1 = H)

N R1

NR2R3

93–97% (R1 = H) 65–96% (R1 = Me)

1 = Me)

TMNT (R

R2 = Me, Et, Prn, Pri, Bun, c-C6H11 R3 = H, Me, Et, Prn, Pri, Bun

Scheme 34

As depicted in Scheme 35, methyl N-aryldithiocarbamates were reported to undergo thiocarbamoyl transfer to aminopyridine derivatives . Thus, when 2-amino-3-carbethoxy4,6-dimethylpyridine was reacted with various methyl N-aryldithiocarbamates in DMF, the expected thiourea derivatives formed and spontaneously cyclized to 3-substituted 2-thioxo-5,7-dimethylpyrido[2,3-d]pyrimidine-4(3H)-ones in 55–69% yields.

CO2Et Me

N

Me

Me

Me

NH2

S +

Ar

N H

DMF SMe

O

CO2Et Me

N

N H

S NHAr

N 55–69%

Me

N

N H

Ar S

Ar = C6H5, 3-Cl-4-F-C6H3, X-C6H4 (X = 4-Me, 4-F, 4-Cl, 3-Cl)

Scheme 35

Thioglycolic acid (a thiocarbamoyl transfer agent which is readily available from carbon disulfide, a primary or secondary amine and sodium chloroacetate salt) affords aminothiocarbonyl hydrazines upon refluxing with hydrazine hydrate in a basic medium. Their thiosemicarbazones were synthesized by refluxing in water with an alcoholic solution of 5-nitrothiophene-2-carboxaldehyde (Scheme 36) . The overall process takes place with moderate yields and some of the resulting products show significant antimoebic or antitrichomonal activity.

561

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms S

S R1R2N

N2H4.H2O S

CO2H

R1R2N

O2N

CHO

S

NHNH2

NaOH ∆

S R1R2N

∆, 53–74%

N N H

NO2

S

R1 = alkyl, cycloalkyl R2 = alkyl, H R1, R2 = –(CH2)6–

Scheme 36

6.18.1.1.9

From sulfur-transfer reagents

The direct introduction of sulfur from S8 into diaminocarbenes—the so-called Arduengo carbene ligands—can be regarded as a useful entry into cyclic thioureas. Thus, Bildstein and co-workers have reported the preparation of imidazolinethiones, imidazolethiones, and benzimidazolethiones by treatment of the corresponding azolium salts with base and elemental sulfur (Scheme 37) .

NHFc

FcHN

X

–

Fc N

+

Fc N

MeLi

S

or N Fc

FcN NFc Fc + N

–

S8, 44–56%

Fc N

KOt Bu X

N CH3

N Fc

S N CH3

S8, 98%

(Fc = ferrocenyl)

Scheme 37

The synthesis of 4-(4-fluorophenyl)-5-(pyridin-4-yl)imidazole-2-thiones, whose alkylthioimidazoles are inhibitors of p38 MAP kinase, can be carried out in moderate to good yields by transfer of sulfur from sodium (4-chlorophenyl)methanethiolate to 2-chloroimidazoles as outlined in Scheme 38 .

Het

R1 N

Ar1

N

Ar2CH2SNa (4.5 equiv.)

Het

R1 N

Ar1

N

Cl

Ar2 –

SCH2Ar2

Het = pyridin-4-yl Ar1 = 4-F-C6H4 Ar2 = 4-Cl-C6H4 R1 = Ph, Prn, c-C6H11, pyridin-3-yl

Scheme 38

R1 N

Ar1

N H

S

S DMF/∆

Het 51–80%

562

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

The employment of ammonium sulfide for a convenient cyclization of -cyano--(dichloromethyleneimino)alkanoic acids, available from the corresponding isocyanides and chlorine, into 5,5-disubstituted 2,4-dithiohydantoins has been described a few years ago (Scheme 39) . The reaction is proposed to occur by addition of sulfide and cyclization to a thiazole ring followed by ring opening and new closure.

Cl

S

(NH4)2S (2)

N R1 Cl CO2R2 NC

N H R1 CO2R2

S

acetone, rt

S

HN

H N

58–75%

S

N H R1 CO2R2

R1 = Me, Et, Bu R2 = But

Scheme 39

In 1998 thioketones were first developed as efficient sulfur transfer agents towards azole N-oxides providing a new synthetic method for the thiourea function (Scheme 40) . Thus, substituted imidazole 3-oxides react with some thioketones (2,2,4,4tetramethyl-cyclobuta-1,3-dithione, 2,2,4,4-tetramethyl–1-thioxo-cyclobutan-2-one, and adamantine-2-thione) to give imidazole-2(3H)-thiones in high yield. Triazole oxides can also be transformed equally well into triazolethiones. O– N

R3 R2

+

+

CHCl3

R

rt 65–96%

R

CHCl3

R

rt 84%

S

N R1

EtO2C

R3

R

–

+

N

O

+

R1 = alkyl R2, R3 = Me, Ph

R2

H N N Ph

S

S

R =

S

S

N R1

EtO2C

S

N Ph

H N

;

S

X

R (X = O, S)

Scheme 40

Taking advantage of this procedure, Laufer and co-workers have synthesized a structurally diverse imidazole thiones during their studies directed to develop new inhibitors of p38 MAP kinase with a 4,5-disubstituted alkylthioimidazole framework (Scheme 41). The required imidazole oxides are obtained in high yields by refluxing in ethanol a mixture of 1-(4-fluorophenyl)-2-(pyridin-4-yl)hydroximinoethan-2-one and the corresponding 1,3,5-trisubstituted hexahydro-1,3,5-triazine. In the course of their studies of adenosine-derived monomeric building blocks for new oligonucleosides, Gunji and Vasella showed the ability of N-phenylthiourea as sulfur-transfer agent to 2-halogenoimidazoles (Scheme 42). Thus, the 2-chloro and 2-iodo nucleosides were transformed into the corresponding thioxo nucleosides upon heating with N-phenylthiourea at 60
C. Molina and co-workers have reported a rather unexpected sulfur-transfer reaction from carbon disulfide which is the basis of a new synthesis of dihydroquinazoline2-thiones (Scheme 43). The process comprises the intramolecular heteroconjugate addition of

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

563

aromatic carbodiimides bearing an o-substituted ,
-unsaturated carbonyl fragment promoted by the carbon disulfide/tetrabutylammonium fluoride. The mechanism proposed by the authors nicely accounts for the complex transformation and involves cyclization induced by attack of the S-nucleophile fluorodithioformate, generated from CS2-TBAF, followed by thioacyl fluoride hydrolysis and fragmentation to the thione group and C(S)O.

Het

(CH2=NR)3

O

Ar

EtOH/∆ 50–89%

NOH

Het

R N

Ar

N – O

S

Het

R N

Ar

N H

S

S

+

CHCl3, rt 60–98%

Het = pyridyn-4-yl Ar = 4-fluorophenyl R = Me, Prn, c-C3H7, R2N(CH2)2, 3, RO(CH2)3

Scheme 41

S OR1 N

N

O

R2

N X O

O

NHBz

N

NHBz

N

PhHN

OR1 N NH2

NH

O

R2

N S

toluene, 60 °C 82–98%

O

O

R1 = Et3Si R2 = Me3Si C C X = Cl, I

Scheme 42

O O R2

N

CS2/ TBAF (4:1)

N C N R1

S

N H

25 °C

R2 R1

40–50% S F

O

+

Bu4N

N R

1 = Ar,

Bn

+

–

–

S

N

–S C O

Bu4N

–TBAF

R2 R1

H2O S

S F

R2 = Fc, OMe

Scheme 43

Finally, N,N-unsubstituted thioureas are accessible in moderate-to-high yield by sulfur transfer from LiAlHSH, generated in situ by mixing LAH and sulfur, to chloroamidines, as depicted in Scheme 44 .

564

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms LiAlHSH

NH HCl R

N R

NH R

Cl

THF, 0 °C

N R

S

SH

R 51–89%

N R

NH2

R = Me, Et R-R = –(CH2)4,5–

Scheme 44

6.18.1.2 6.18.1.2.1

Thiocarbonyl Derivatives with One Nitrogen and One Phosphorus Function From isothiocyanates

The addition of the PH bond of phosphines to isothiocyanates, as well as the lone pair of substituted phosphines, continues to be the most valuable method for preparing phosphinothioformamides. For instance, bis(2-phenethyl)phosphine adds to 2-(vinyloxy)ethyl isothiocyanate under thermal reaction conditions to produce the expected N-(2-vinyloxyethyl thiocarbamoyl)phosphine in excellent yield. Similarly, the addition of the phosphine oxide analog to the isothiocyanate and stirring in refluxing benzene results in the formation of the corresponding N-(2-vinyloxyethylthiocarbamoyl)phosphine oxide (Scheme 45) . O S R2P

R2PH NHR1

R2P R1 N C S

70 °C, 90%

H

C6H6, reflux, 95% R2P O

S NHR1

R = PhCH2CH2 R1 = CH2=CH-O-CH2CH2

Scheme 45

Phosphines bound to transition metals have frequently been reacted with isothiocyanates in order to effect structural modification on the coordination sphere in phosphine-containing metal complexes. Malisch and co-workers have prepared various P-mesitylferrio(thiocarbamoyl)phosphines by reaction of P-mesitylferriophosphine with alkyl and phenyl isothiocyanates (Scheme 46). The thiocarbamoylphosphines thus obtained were in turn P-alkylated with alkyl halides or oxidized with elemental sulfur. In addition, the authors communicated that the ferrio-(t-butyl)phosphine analog reacts with 2 equiv. of methyl and ethyl isothiocyanate to produce P-thiocarbamoylphosphametallacycles (Scheme 46). The formation of these adducts can be rationalized by formal [3+2]-cyclization of isothiocyanate and the metal complex, via the phosphine and CO ligands, followed by insertion of the second molecule of heterocumulene into the PH bond . Molybdenum and tungsten phosphenium complexes Cp(CO)2M¼PH-t-Bu undergo a [2+2]cycloaddition reaction to alkyl isothiocyanates furnishing the four-membered phosphametallacycles. Furthermore, insertion of the isothiocyanate into the PH bond of these systems occurs and the corresponding thiocarbamoyl phosphine derivatives are obtained in high yields (Scheme 47) . In a closely related process, deprotonation of the dinuclear phosphine complex shown in Scheme 47, followed by addition of phenyl isothiocyanate and nitrogen protonation gives the expected complex in 85% yield . The ferrio-diphenylphosphine Cp(CO)(PMe3)Fe-PPh2, formed from Cp(CO)2Fe-PPh2 by CO/ PMe3 ligand exchange, readily adds to methyl isothiocyanate giving rise, after protonation with triflic acid, to the cationic open-chain thiocarbamoylphosphine iron complex (Scheme 48) . Structurally related complexes of iron and ruthenium, formed in situ by deprotonation of their cationic precursors with KO-t-Bu, add to methyl isothiocyanate to

565

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

generate an open-chain adduct, which suffers further cyclization by means of nucleophilic addition to a carbonyl ligand (Scheme 48) . The corresponding acyclic addition product would be available by acid treatment.

R S

R1NCS

Mes Cp(CO)2Fe P H

S R2 P NHR1 X Mes

Cp(CO)2Fe

2X

Cp(CO)2Fe

P NHR1 Mes

R1 = Me, Et, Ph Mes = mesityl

t Cp Bu

2RNCS Cp(CO)2Fe-PH-But R = Me, Et

O

N R

NHR1

S

OC Fe P

toluene 25 °C, 69–76%

S

Mes Cp(CO)2Fe P S

S

NHR S

Scheme 46

RNCS Et3N

H [M]

H t P Bu

[M]

P

toluene 25 °C

But

S RNCS 74–93%

S

NHR P But

[M] S

N R

N R

[M] = Cp(CO)2Mo, Cp(CO)2W

R = Me, Et, But P

P Cp(CO)2Mo

Mo(CO)Cp PHPh2

i. DBU ii. PhNCS, 25 °C

P Cp(CO)2Mo

iii. HBF4, 85%

P Mo(CO)Cp

Ph2P

NHPh S

Scheme 47

S i. MeNCS

Cp(Me3P)(CO)FeP NHMe Ph Ph

Cp(CO)(PMe3)FePPh2 ii. TFA

+

Cp(CO)2M-PHR1R2 M = Fe, Ru R1 = But, Pri, Ph

X

–

KOBut Me-NCS

toluene 25 °C, 68–83%

Cp

R1

S

OC M P R2 O

+

N Me

R2 = But, Pri, Ph

Scheme 48

S

HX M = Fe R1 = Ph R2 = Ph 98%

+

Cp(CO)2FeP NHMe X Ph Ph

–

566

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

Majoral and co-workers have carried out an extensive study on the reactivity of bi- and tricyclic -zirconated phosphanes and various cumulenes, e.g., isothiocyanates (Scheme 49). Thus, -phosphinozirconacycles and methyl and phenyl isothiocyanates afford stable zwitterionic tri- and tetracyclic five-membered anionic zirconium complexes in moderate-to-high yields.

RNCS

+

–

PPh2

Zr

Cp

Cp

toluene 25 °C, 53–73%

Cp Zr Cp N R

PPh2 S

R = Me, Ph

PhNCS P

Zr Cp

Cp

Ph

toluene – 40 °C, 91%

P Ph Cp Zr Cp N S Ph

Scheme 49

Interestingly, the PSi bond is capable of inserting into the C¼N bond of isothiocyanates in the same way as does the PH bond. This makes it feasible to prepare unconventional systems such as thiocarbamoyl phosphaalkenes, as reported by Weber and co-workers (Scheme 50) . The reaction of the phosphaalkene (Me2N)2C¼P-SiMe3 with phenyl isothiocyanate in pentane at low temperature furnishes the expected adduct in 72% yield.

Me2N P SiMe3

P pentane –30 °C, 72%

Me2N

S

Me2N

PhNCS

Me2N

N Ph

SiMe3

Scheme 50

Cyclic systems, such as thioxoazaphospholes, have recently been described by Ruiz and co-workers (Scheme 51) . They started with the diphosphanyl ketenimine, which was first transformed into the monooxidized derivative by crystallization-induced cyclodimerization, followed by H2O2 oxidation and thermal dedimerization. The oxidized diphosphanyl ketenimine behaves as a 1,3-dipole towards ethyl isothiocyanate affording the [3+2]-cycloadduct in 70% yield.

i. Crystall. Ph2P C C N Ph Ph2P

O

O

ii. H2O2

Ph2P

iii. Toluene reflux 81%

Ph2P

C C N Ph

EtNCS toluene reflux 70%

N Ph

Ph2P N Et Ph P Ph S

Scheme 51

6.18.1.2.2

From halothioamides

A facile synthesis of diphenylphosphino-N,N-dimethylthioamide, a simple and useful ligand in organometallic chemistry, has been achieved in moderate yield and comprises the treatment of sodium diphenylphosphide with dimethylthiocarbamoyl chloride (Scheme 52) .

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms i. Na / THF Ph2PH

567

S NMe2

Ph2P

S ii. NMe2

Cl

THF, 25 °C 55%

Scheme 52

6.18.1.2.3

From thiophosphinoyldithioformates

No relevant new work .

6.18.1.2.4

has

been

reported

in

this

area

since

COFGT

(1995)

From phosphonodithioformates

A large number of phosphonate derivatives have been reported by amination of methyl phosphonodithioformates with primary and secondary amines as well as with ammonia (Scheme 53) . S (RO)2P

S

R1R2NH (RO)2P

SH

O

NR1R2

O R1 = R2 = H; R1 = H, R2 ≠ H; R1, R2 ≠ H

Scheme 53

6.18.1.2.5

Miscellaneous methods

Renard and Mioskowski have utilized various phosphorus reagents to create phosphorus–sulfur bonds. Accordingly, the synthesis of a number of phosphonothioates is readily achieved by the reaction of the phosphorus precursors with alkylthiocyanates in the presence of the hindered, nonnucleophilic base phosphazene P4-t-Bu (Scheme 54, via A) . Unexpectedly, the heating of ethoxyphenyl phosphinate with cyclohexylthiocyanate in the presence of diisopropylethylamine, instead of phosphazene, results in the exclusive formation of the (cyclohexylamine)thioxomethyl phosphinate derivative (via B). Obviously, the formation of the thiocarbamoylphosphine derivative requires that the phosphorus–carbon bond formation be preceded by the thermal isomerization of cyclohexylthiocyanate to cyclohexylisothiocyanate.

c-C6H11 S C N

via A

+

O Ph P H OEt

via B Pr2NEt EtO DMF 110 °C 78%

Phosphazene P4-t-Bu 82%

O Ph P S c-C6H11 OEt

Scheme 54

Ph P O

S NH-c-C6H11

568

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

According to Morita and co-workers , different phosphine carbothioamides are available in moderate yields by heating tetrazolylsulfinylmethyl(dimethyl)phosphine oxide in the presence of primary and secondary amines (Scheme 55). The resulting compounds are thought to be formed by the addition of amines to the sulfine formed initially, followed by elimination of water.

Ph N

N N N

-

Ph N

N N N

O S

S

R1R2NH

O PMe2

R1R2N dioxane 70 °C 50–53%

R1R2NH –H2O

O

H S H

PMe2 O

PMe2 O

Scheme 55

6.18.2

FUNCTIONS CONTAINING AT LEAST ONE METALLOID FUNCTION

This class of compounds is very rare in the literature. In fact a few examples of silicon-containing derivatives were collected in the COFGT (1995) report. In the present update review, isolated systems containing two phosphorus functions and two silicon functions are given.

6.18.2.1

Thiocarbonyl Derivatives with Two Silicon Functions

Bis(trimethylsilyl)thioketone S-oxide represents certainly an island in the context of this sort of silicon functionality. In this particular case, tris(trimethylsilyl)methyllithium was reacted with SO2 in THF to provide that functional system in 41% yield (Scheme 56) .

O S (Me3Si)3C-Li +

SO2 THF 41%

Me3Si

SiMe3

Scheme 56

6.18.2.2

Thiocarbonyl Derivatives with Two Phosphorus Functions

Taking advantage of the reversible SS bond breaking and bond formation in dinuclear complexes of Mn(I) containing the disulfide function, Ruiz and co-workers have reported a method for accessing a mononuclear (diphosphanylthioketone)manganese complex (Scheme 57). Thus, the starting disulfide-containing dinuclear complex 5 transformed instantaneously into the sulfenyl iodide mononuclear complex 6 upon treatment with 1 equiv. of iodine. Further iodide abstraction by using either excess of iodine or TlPF6 produces the desired diphosphanylthioketone complex 7. The direct conversion of the disulfide 5 into 7 was accomplished by oxidation of the sulfur–sulfur bond with 2 equiv. of AgBF4.

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms Ph

Ph

I2

P (CO)4Mn

Ph

Ph

Ph

Ph P 2 (CO)4Mn

S P

CH2Cl2 2

569

S

I

P Ph

Ph 6

5 AgBF4 CH2Cl2

I2 or TIPF6

–Ag +

40%

Ph

Ph P 2 (CO)4Mn

S P

Ph

Ph

7

Scheme 57

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Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

571

Biographical sketch

Jose´ Barluenga studied chemistry at the University of Zaragoza and received his doctorate in 1966. He spent three and a half years as a postdoctoral research fellow of the Max Planck Gesellschaft at the Max Planck Institut fu¨r Kohlenforschung (Mu¨lheim a.d. Ruhr, Germany) in the group of Professor H. Hoberg. In 1970 he became Research Associate at the University of Zaragoza where he was promoted to Associate Professor in 1972. In 1975 he moved to the University of Oviedo as Professor in Organic Chemistry, where he is currently Director of the Instituto Universitario de Quı´ mica Organometa´lica ‘‘Enrique Moles.’’ His major research interest is focused on developing new synthetic methodologies in organic chemistry by means of organometallic reagents as well as iodine-based systems.

Eduardo Rubio (Logron˜o, Spain, 1959) received his B.A. degree in Oviedo and got his Ph.D. under the supervision of Professors Barluenga and Toma´s in 1989. He carried out postdoctoral studies at MIT (Alex Klibanov, enzymes in organic solvents, 1989–1990) and at the University of California, Berkeley (Peter Vollhardt, organic synthesis mediated by organometallic reagents, 1990–1991). He returned to the University of Oviedo and got a position as Profesor Titular in 1996. From 2000 he is the secretary of the Instituto Universitario de Quı´ mica Organometa´lica ‘‘Enrique Moles,’’ where he continues his research. His main research interests are synthetic and mechanistic chemistry and the application of NMR to the study of reaction mechanisms.

572

Functions Containing a Thiocarbonyl Group Bearing Two Heteroatoms

Miguel Toma´s received his B.A. degree in chemistry from the University of Zaragoza in 1974 and his Ph.D. degree from the University of Oviedo in 1979. He was a postdoctoral fellow (1981–1983) in the research group of Professor A. Padwa at Emory University (Atlanta, USA) working on 1,3-dipolar cycloadditions. Then, he returned to the University of Oviedo where he was appointed Profesor Titular in 1985 and promoted to Professor of Organic Chemistry in 1996. His major research encompasses the use of transition metal reagents, particularly metal carbene complexes, as flexible intermediates in organic synthesis and the design of new metal-catalyzed processes.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 545–572

6.19 Functions Containing a Selenocarbonyl or Tellurocarbonyl Group—SeC(X1)X2 and TeC(X1)X2 L. J. GUZIEC and F. S. GUZIEC, Jr. Southwestern University, Georgetown, TX, USA 6.19.1 OVERVIEW 6.19.2 SELENO- AND TELLUROCARBONYL FUNCTIONS CONTAINING AT LEAST ONE ATTACHED HALOGEN 6.19.2.1 Seleno- and Tellurocarbonyl Compounds Containing Two Attached Halogen Atoms 6.19.2.2 Seleno- and Tellurocarbonyl Compounds Containing One Attached Halogen Atom 6.19.3 SELENOCARBONYL FUNCTIONS CONTAINING AT LEAST ONE ATTACHED CHALCOGEN (AND NO HALOGENS) 6.19.3.1 Dialkoxy-substituted Selenocarbonates (RO)2C¼Se 6.19.3.2 Dithio-substituted Selenocarbonates (RS)2C¼Se 6.19.3.3 Diseleno-substituted Selenocarbonates (RSe)2C¼Se 6.19.3.4 Selenocarbonyl Functions Flanked by Two Different Chalcogen Atoms RX(C¼Se)Y 6.19.3.5 Selenocarbamates RO(C¼Se)NHR, RS(C¼Se)NHR, RSe(C¼Se)NHR, RTe(C¼Se)NHR 6.19.4 FUNCTIONS CONTAINING AT LEAST ONE NITROGEN FUNCTION (AND NO HALOGEN OR CHALCOGEN FUNCTIONS) 6.19.4.1 Selenoureas (R2N)2C¼Se 6.19.4.2 Other Cyclic N(C¼Se)N Compounds 6.19.4.3 Telluroureas (R2N)2C¼Te 6.19.5 HYPERVALENT SELENOCARBONYL COMPOUNDS OF THE TYPE Se¼C(X)X0

6.19.1

573 574 574 574 576 576 576 578 580 581 584 584 588 590 591

OVERVIEW

As previously reported in chapter 6.19, COFGT (1995) , seleno- and tellurocarbonyl derivatives of common carbonyl-based functional groups are much less well known than their corresponding oxygen or sulfur analogs. The comparative rarity of the seleno- and tellurocarbonyl compounds has been primarily due to their decreased stability as a result of poor
-overlap in C¼Se and C¼Te bonds. In the period 1993–2003 ingenious use of new reactions and novel reagents have made previously rare structures much more readily available for investigation. Particularly noteworthy in this period are reports of hypervalent halogen adducts of selenocarbonyl compounds, a topic not originally covered in COFGT (1995) . 573

574 6.19.2

6.19.2.1

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group SELENO- AND TELLUROCARBONYL FUNCTIONS CONTAINING AT LEAST ONE ATTACHED HALOGEN Seleno- and Tellurocarbonyl Compounds Containing Two Attached Halogen Atoms

Compounds containing a halogen atom directly attached to a seleno- or tellurocarbonyl function remain quite rare . Both selenocarbonyl difluoride 1 and tellurocarbonyl difluoride 2 have been prepared by careful reaction of mercury salts with Lewis acid. Both of these compounds are unstable and rapidly dimerize. The reactivity of the tellurocarbonyl compound greatly exceeds that of the corresponding selenocarbonyl species. An improved method for the preparation of monomeric tellurocarbonyl difluoride involves pyrolysis of the stannyl telluride (Equation (1)) . Dimerization to the corresponding ditelluretane rapidly occurs at temperatures above 77 K. Co-condensation of 1 and 2 affords the mixed selenium– tellurium dimer. In situ generated tellurocarbonyl difluoride can also be trapped as its cycloaddition product with 2,3-dimethylbutadiene (Scheme 1).

F

F

Se

Cl

Te

Se

F

F

1

Cl 3

2

i

F

Me3SnTeCF3

Te

> –196 °C

F

50–60%

F

Te F

F

Te F

ð1Þ

i. FVP, 280 °C

F Se F F Te

F

Te F

F

Se F

F Te F F

Scheme 1

Selenophosgene 3 has been suggested as an intermediate in Willgerodt–Kindler-type reactions of trichloroacetic acid or chloroform with base and elemental selenium in the presence of amines to form selenoureas (see Equation (30)).

6.19.2.2

Seleno- and Tellurocarbonyl Compounds Containing One Attached Halogen Atom

N,N-Dimethylselenocarbamoyl chloride 4 can be prepared quantitatively by treatment of dichloromethylene dimethyliminium chloride with lithium aluminum dihydroselenide (Equation (2)) . This selenocarbamoyl chloride is an extremely useful reagent for the preparation of diselenocarbamates, thioselenocarbamates, and selenoureas (see Sections 6.19.3.5 and 6.19.4.1). The conversion of other dialkyliminium salts into the corresponding selenocarbamoyl chlorides should significantly simplify the preparation of a variety of other interesting selenocarbonyl compounds.

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group

Me2N CCl2

Cl

LiAlHSeH, 0 °C

Se Me2N C Cl

Quantitative

4

575

ð2Þ

A number of unstable selenocarbonyl fluorides can be prepared by treatment of perfluorinated mercuric selenides with diethylaluminum iodide or aluminum iodide (Equation (3)) . These compounds rapidly polymerize, but the polymers upon heating can be converted to the monomeric or dimeric materials. The monomeric selenocarbonyl compounds can be trapped by cycloaddition with cyclopentadiene (Scheme 2). Se

Et2AlI

(RSe)2Hg

Se F

R

R = CF3CF2CF2–, CF3CF2–, CF3–

R

F

n

ð3Þ

R = CF3CF2–, CF3–, CF3Se–

∆

Se

F

R

35 – 45%

Se R

n

R

Se R

F

Se F

F R

R = CF3CF2–, CF3–

Se

F

Scheme 2

Flash vacuum pyrolysis (FVP) of perfluorinated trimethyltin tellurides affords isolable tellurocarbonyl fluorides which dimerize at low temperature to the corresponding ditelluretanes 5 (Equation (4)) . The tellurocarbonyl fluorides can also be trapped as their cycloadducts with dienes (Equation (5)) . Although no tellurocarbonyl analogs of acyl chlorides have been reported, the ‘‘dimeric’’ dichloroditelluretane 6 can be isolated by reaction of the difluoro compound with boron trichloride (Equation (6)).

Me3SnTeR

Te

FVP F

R1

> –196 °C

R1

Te R1

49–64%

F

Te F 5

R = CF3CF2–, CF3CF2CF2–, CF3(CF2)2CF2–

ð4Þ

R1 = CF3–, CF3CF2–, CF3CF2CF2–

Te Me3SnTeCF2CF2CF3

F CF3CF2

160 °C

Te F Te CF2CF3

Te CF3CF2

F

– 40 °C to 22 °C BCl3 82%

ð5Þ

F CF2CF3

75%

Cl CF3CF2

Te Cl Te CF2CF3 6

ð6Þ

576 6.19.3

6.19.3.1

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group SELENOCARBONYL FUNCTIONS CONTAINING AT LEAST ONE ATTACHED CHALCOGEN (AND NO HALOGENS) Dialkoxy-substituted Selenocarbonates (RO)2C¼Se

Dialkoxy-substituted selenocarbonyl compounds remain quite rare in the literature . O,O-Diethylselenocarbonate 7 has been prepared from tetraethylorthocarbonate by the use of bis(dimethylaluminum)selenide (Equation (7)) . Attempts at using this reagent for the direct conversion of the carbonyl group to the selenocarbonyl group in other related compounds were unsuccessful.

(EtO)4C

(Me2Al)2Se

+

Toluene, dioxane 80 °C

Se EtO

74%

ð7Þ

OEt 7

6.19.3.2

Dithio-substituted Selenocarbonates (RS)2C¼Se

A variety of synthetic routes have been available for the preparation of cyclic dithio-substituted selenocarbonates, important precursors for the synthesis of tetrathiafulvalenes . A number of routes for the preparation of these selenocarbonates start from the corresponding thiocarbonyl compounds. Selective S-alkylation followed by treatment with sodium hydrogen selenide affords the desired selenocarbonyl derivatives in good yield (Equation (8)) . Some additional examples of this transformation in the preparation of various complex dithio-substituted selenocarbonates have also appeared (Equation (9)) . The utilization of the selenocarbonate–diene intermediate 8 appears to be a particularly interesting approach for the introduction of the dithioselenocarbonate moiety into complex molecules (Scheme 3) . O

O S

Ph

i. CF3SO3CH3 ii. Se, NaBH4, PhCOCl

S S

Ph

S

S

Ph

S

ð8Þ

Se

S

76%

O

Ph

S

S

O

S

i–iii

S Se

S S

S

ð9Þ

i. CF3SO3Me, 91%; ii. Se, H2O, NaBH4; iii. AcOH, toluene, 59% for two steps

The thiocarbonyl group of a cyclic trithiocarbonate group can also be converted to the corresponding selenocarbonyl moiety using triethyl orthoformate in the alkylation step (Scheme 4) . Subsequent base promoted cyclization afforded thieno[2,3-d]-1,3-dithiol-2-selone 9. Related heterocyclic dithioselenocarbonates could be readily incorporated into the corresponding complex tetrathiafulvalenes . A variety of complex heterocyclic dithioselenocarbonates have also been prepared using the reaction of N,N-dialkyldithiocarbamate salts with sodium hydrogen selenide (Schemes 5 and 6) .

577

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group S

HO HO

i–iii S

76%

S

S

HO HO

iv Se

58%

S

S

Br Br

Se S v

S Se S

C60

S

25%

S

Se 8

i. MeI, THF, 91%; ii. Se, H2O, NaBH4; iii. AcOH, toluene; iv. PBr3, THF, CCl4; v. KI, 18-crown-6, toluene

Scheme 3

O S

MeO

O

i. HC(OEt)3, BF3·Et 2O ii. NaHSe

S

S

MeO

S

S

Se

S

MeO

S

MeO

27%

O

O i, ii Quantitative S

MeO

S

O H O

Se

S

i. NaOMe; ii. H+

9

Scheme 4

O

O S

HN H2N

i, ii

+

NEt2 N

HN

76%

S

H2N + N H

ClO4

Se S C NEt2

O iii, iv 50%

S

S

HN H2N

Se N

i. Na2Se; ii. AcOH; iii. HCl, AcOH, heat; iv. DMF, pyridine, H2O

Scheme 5

O Me O

N N Me

S S C NEt2

O Me

i. Conc. H2SO4 ii. NaClO4

O

S

N

O

S

N Me

ClO4

i 66% O Me O

S

N

Se N Me

S

Scheme 6

+

NEt2

i. Na2Se, H

+

S

578

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group

The metallation–chalcogenation sequence performed on the mixed sulfur–selenium substituted thione 10 leads to a ‘‘Dimroth rearrangement’’ affording the selenocarbonyl complex, which can be further transformed into other selenocarbonate derivatives (Scheme 7) .

S S Se

Se

i–iv 32%

S

(Bu4N)2 Zn

v

Se Se

S

S

PhCOSe

S

Se

61%

2

PhCOSe

10 i. LDA / THF, –78 °C, 2 h; ii. Se, –78 °C 1 h, rt, 2 h; iii. ZnCl2 , MeOH, NH3; iv. Bu4NBr, MeOH; v. PhCOCl, acetone

Scheme 7

6.19.3.3

Diseleno-substituted Selenocarbonates (RSe)2C¼Se

Cyclic triselenocarbonates are important intermediates in the synthesis of tetraselenafulvalene derivatives and numerous methods have been used in the preparation of these compounds . A novel approach to the preparation of the unsymmetrical triselenocarbonate 11 involves metallation of the protected acetylene followed by consecutive treatment of the lithium salt with selenium, carbon diselenide, and methyl iodide (Equation (10)) . A variety of other triselenocarbonate derivatives including bridged bis(1,3-diselenole-2-selones) 12 have also been prepared using this procedure (Equation (11)) . OTHP

OTHP

Se

i–iv Se

Se

70%

SeMe

11

ð10Þ

i. BunLi, TMEDA, THF, –70 °C ii. Se, 0 °C iii. CSe2, Se, –70 °C iv. MeI

i. BunLi, THF

Se Se

ii. Se, 0 °C

( CH2)

S C CH

n S C CH

iii. CSe2,

S

Se

n S

Se

( CH2)

51–58%

ð11Þ Se

Se 12

The lithium intermediate in this reaction can also be trapped by the addition of an alkyl isothiocyanate introducing a sulfur substituent on the diselenole-2-selone ring (Equations (12) and (13)) . This lithium intermediate can also be generated by metallation of 1,2-dichlorovinylmethyl sulfide . The potential versatility of these methods has been shown with the use of the acetylenic silane in this transformation (Scheme 8) . i, ii, iii Me S C CH

73%

Se

SMe

Se

S

Se

O OMe

i. BunLi, –78 °C, THF; ii. Se; iii. CSe2; iv. MeO2CCH2CH2SCN

ð12Þ

579

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group

HC C

i–iv

S

S

Se

OTHP

OTHP

Se Se

71–73%

SR

ð13Þ

i. BunLi, TMEDA, –70 °C ii. Se, 0 °C iii. CSe2, –90 °C iv. RSCN

i, ii, iii Me3Si

SiMe3

Se

C CH

+

Se Se

i. BunLi, –78 °C, THF; ii. Se, 0 °C

Se

SiMe3

Se

S

O

Se

OMe

(Bun)4NF

iii. CSe2, –90 °C, MeO 2CCH2CH2SCN Se

Se +

Se

O

Se

Se

Se

S

OMe

66%

Scheme 8

Reactions of iminium salts with hydrogen selenide are widely used in the preparation of triselenocarbonates. This route has been used for the preparation of triselenocarbonates containing a 13C labeled selenocarbonyl group (Scheme 9) .

Se

i, ii

N * Se

O

Se * Se

+ N

86%

Se * Se

iii 53%

Se

PF6– i. H2SO4; ii. HPF6; iii. H2Se, EtOH * denotes 13C

Scheme 9

Electrochemical reduction of carbon diselenide provides a convenient route to the diseleniumsubstituted diselenol-2-selone (Scheme 10) .

2 e–

2 CSe2

–

Se

–

Se

Se Se

CSe2

Se

Se

Se

–CSe3–2

Se

2 e–

Se

Se–

Se

Se–

Se

Se

Bun4 NBr, ZnCl2 82% Se Se Se

Se Se

CO2Me CO2Me

Br(CH2)2CO2Me

Se

Se

Se

Se

Zn

Se 82%

Scheme 10

2

(Bun4 N)2

580

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group

Cyclooctyne reacts with carbon diselenide in the presence of selenium to afford the corresponding triselenocarbonate 13 (Equation (14)) . +

Se

CH2Cl2, reflux

CSe2 + Se

Se Se

59%

ð14Þ

13

6.19.3.4

Selenocarbonyl Functions Flanked by Two Different Chalcogen Atoms RX(C¼Se)Y

Compounds with the selenocarbonyl group attached to two different chalcogen atoms have until the late 1990s been relatively rare . Increased interest in mixed fulvalene derivatives has led to novel approaches for the preparation of these compounds. The abovementioned metallation route to diselenole-2-selones (Section 6.19.3.3, Equations (10)–(13)) can be readily applied to the preparation of the corresponding sulfur–selenium heterocycles. Treatment of the protected lithiated acetylene with sulfur followed by carbon diselenide and selenium and trapping with ethyl iodide affords the desired selenocarbonate 14 (Equation (15) . This method was also used for the preparation of novel 1,3-selenatellurole2-selones such as 15 (Equation (16)) . Extension of this reaction to other substituted acetylenic precursors and trapping with various electrophiles should make this method a very versatile route to the mixed chalcogen-substituted selones. HC C

S

S

Se

i–iv

OTHP

OTHP

Se

73%

S

SeEt

i. BunLi, TMEDA, –70 °C

ð15Þ

14

ii. S, 0 °C iii. CSe2, –90 °C iv. Se, EtI, 0 °C Me3Si

Te

i–iv

C CH

83%

Se Se

ð16Þ

15 i. BunLi; ii. Te; iii. CSe2; iv. H2O

Another interesting metallation route affords the mixed sulfur–selenium heterocyclic selenocarbonate 16 via an iminium salt intermediate (Scheme 11) . A similar reaction of an iminium salt with hydrogen selenide affording a related selenocarbonate has also been reported . O O

O

i

O

O

Li

O

ii, iii 68%

Se

N S

O

iv, v

O

vi

Se

O

Se

Se S

O

+

N 11%

O

O

S Br –

16

i. BuLi (1 equiv.), 0 °C; ii. Se, THF, –35 °C; iii. morpholino-4-thiocarbonyl chloride, –78 °C; iv. Br2, CH2Cl2; v. 110 °C; vi. Se, NaBH 4, AcOH–EtOH

Scheme 11

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group 6.19.3.5

581

Selenocarbamates RO(C¼Se)NHR, RS(C¼Se)NHR, RSe(C¼Se)NHR, RTe(C¼Se)NHR

A variety of methods have been described for the preparation of selenocarbonyl derivatives of urethanes . Since 1995 there has been significantly increased interest in developing new synthetic methods in this area. Treatment of N,N-dimethylselenocarbamoyl chloride (Section 6.19.2.2) with readily prepared lithium thiolates and selenolates provides a convenient route to N,N-dimethylamino-substituted thioseleno- and diselenocarbamates (Scheme 12) . The use of other substituted selenocarbamoyl chlorides should make this a very useful general method for the preparation of other interesting selenocarbamate derivatives. +

Me2N CCl2

Cl–

LiAlHSeH, 0 °C

Se Me2N C Cl

RSeLi

RSLi

Se Me2N C SeR

Se Me2N C SR

R = aryl, alkyl 51–95%

R = aryl, alkyl 66–74%

Scheme 12

A general synthesis of O-alkylselenocarbamates involves a convenient one-pot procedure for the preparation of the key intermediate isoselenocyanates (Scheme 13). The reactions occur in high yield and can be used for the preparation of O-alkylselenocarbamates derived from primary, secondary, and tertiary alcohols. The reaction also proceeds in an intramolecular manner to afford the cyclic selenocarbamate 17 (Equation (17) . O H R N C H

i RNH2

ii

iii R N C Se

R N C

R = alkyl, aryl O i. EtO C H, reflux, 12 h

R1OK

ii. Ph3P, Et3N, CCl4, 70 °C; iii. Se, Et3N Se R1O C N R H

Scheme 13 OH

Et3N, THF +

NC

HN

Se 80%

O

ð17Þ Se 17

The first report of the preparation of selenotellurocarbamic esters has appeared . Treatment of an acylisoselenocyanate with excess alkyl tellurol affords the selenocarbonyl Te-alkyl urethane 18 in yields of 20–40% (Equation (18)). O

O

Se

THF N C Se

+

RTeH –80 °C 20–42%

N H 18

TeR

ð18Þ

582

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group

An aryl selenocarbamate prepared from the aryl isoselenocyanate is an intermediate in the ‘‘dehydration’’ of the very sensitive -amino acid 19 (Equation (19)). N C Se OH

i.

NO2, Bun P 3

ð19Þ H N

CO2Et t-BOC

H N

ii. H2O2

CO2Et t-BOC

90%

19

Chiral oxazolidine-2-selones have proved to be useful as derivatizing agents for nuclear magnetic resonance (NMR) determination of chirality due to the extraordinary sensitivity of the 77 Se chemical shift to the chemical environment. Details of the preparation of a variety of these compounds by directed metallation of readily available 2-oxazolines have been reported . (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-selone 20 has proved to be particularly useful for determination of chirality . The rapid reaction of this compound with an acid chloride or with an acid in the presence of a coupling reagent affords chiral oxazolidine-2-selones suitable for NMR analysis (Scheme 14) .

N

i. LHMDS ii. Se iii. Citric acid

O

Me

Se HN

Ph

O

Me

i, ii

BOC

H3C N HH*

O

Se N

O

Me

Ph

Ph

20 H CH3 N C * CO2H ii. DCC, DMAP i. BOC H

Scheme 14

Interesting ‘‘non-Evans’’ stereoselectivity has also been noted in aldol reactions of the readily prepared N-acyl oxazolidine-2-selones 21 (Scheme 15) . This stereoselectivity and the above-mentioned sensitivity of the Se chemical shift to remote stereochemical centers in this heterocyclic system have been explained by unusual C
H Se¼C interactions which have been detected spectroscopically . Se

O N

O

i–iii

N R

R1

O

Se

OH O iv

R3

2

N

O

R2 R1 21

R1 v 98%

i. LiHMDS, –78 °C; ii. Se; iii. R1CH2COCl; iv. R3CHO-TiCl4; v. LiBH4

OH R3

OH R2

Scheme 15

A convenient conversion of the thiocarbonyl group of a thiocarbamate to the corresponding selenocarbonyl moiety involves treatment of the thiocarbonyl compound with triethyl orthoformate and boron trifluoride etherate followed by addition of sodium hydrogen selenide (Equations (20)–(22)) (cf. Section 6.19.3.2, Scheme 4).

583

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group R2

i. BF3-ether, HC(OEt)3, CHCl3 ii. NaHSe, EtOH

S

R2

S

S R

Se

N R1

2

2

79–96%

R

N R1

ð20Þ

R1 = Me, Ph R2 = CO2Me, CN R N

EtO2C

EtO2C

i. BF3–ether, HC(OEt)3 reflux

R N Se

S ii. NaSeH, EtOH, rt

S

Me

Me

S

ð21Þ

R = CH3, CH2CO2Et Me

Me N

i. BF3–ether, HC(OEt)3 reflux

N

ii. NaSeH, EtOH, rt

Se

S

ð22Þ

Se

Se

95%

Alkylation followed by hydrogen selenide treatment also provides a route to selenocarbamates from the corresponding thiocarbonyl compounds (Equation (23)) . The alkylation–hydrogen selenide procedure can also be carried out starting from imines . R1

O R2

N

ii. H2Se

S

S

O

R1

i. Me2SO4

R2

N S

Se

ð23Þ

R1 = alkyl, R2 = Ph, PhCH=CH yields 18–78%

Treatment of methyl thiocyanate with HCl affords the iminium salt which upon treatment with lithium aluminum hydrogen selenide affords the corresponding thioselenocarbamate (Equation (24)) . Se CH3 S C NH2

i. HCl, THF, 0 °C CH3 S C N

ð24Þ

ii. LiAlHSeH 51%

Bis(N,N-dialkylselenocarbamoyl)triselenides 22 can be prepared by reaction of chloroform (or sodium trichloroacetate) with secondary amines and elemental selenium in hexamethylphosphoramide (HMPA) in the presence of sodium hydride (Equation (25)) . Tetra-substituted selenoureas are also formed in this reaction, but the amounts of selenoureas formed can be controlled by temperature and the number of equivalents of amine used (cf. Section 6.19.4.1, Equation (28)). Et2NH

+

Se

Se

NaH, CHCl3, rt Et2N

Se Se

46%

Se Se

ð25Þ

NEt2

22

N,N-Dimethylformamide dimethylacetal reacts with elemental selenium to give a mixture of methyl N,N-dimethylselenocarbamate and the isomeric Se-methyl carbamate (Equation (26)) . Se (MeO)2CHNMe2 + Se

O

Xylene, reflux Me2N

O 22%

Me

+

Me2N

Se 33%

Me

ð26Þ

584 6.19.4

6.19.4.1

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group FUNCTIONS CONTAINING AT LEAST ONE NITROGEN FUNCTION (AND NO HALOGEN OR CHALCOGEN FUNCTIONS) Selenoureas (R2N)2C¼Se

Selenoureas remain the most widely documented selenocarbonyl compounds. Thioureas can be converted to selenoureas by alkylation followed by careful displacement using sodium hydrogen selenide. Reactions of isoselenocyanates with amines, addition of hydrogen selenide to carbodiimides, and displacements of activated vinyl halides by selenourea also provide convenient general routes to selenoureas . Reactions of isoselenocyanates with amines continue to provide one of the most convenient routes to selenoureas (Equation (27)) . N

C

Se +

H H N C N CH2R Se

H2NCH2R

ð27Þ

80–92%

Treatment of N,N-dimethylselenocarbamoyl chloride (Section 6.19.2.2) with secondary or primary amines proves a convenient route to N,N-dimethylamino-substituted selenoureas. Extension of this method to the preparation of other N,N-disubstituted selenocarbamoyl chlorides should make this a very useful general method for the preparation of di-, tri-, and tetrasubstituted selenoureas (Equation (28)) . Se Me2N C Cl

R1

Se R1 Me2N C N R

rt N H

R R,

R1 = alkyl,

ð28Þ

75–95%

R1 = alkyl, R = H, 27–55%

N,N-Disubstituted selenoureas can be prepared in very good yields by treatment of N,Ndialkylaminocyanamides with HCl followed by treatment with lithium aluminum dihydrogen selenide (Scheme 16) . They can also be prepared by the direct reaction of the corresponding cyanamides with highly toxic gaseous hydrogen selenide generated from aluminum selenide in the presence of sulfuric acid . R1 N C N

HCl, THF, 0 °C

R

R1

+

N C NH2 R Cl

–

Cl

LiAlHSeH

R1

70–91%

R

Se N C NH2

Scheme 16

N,N0 -Disubstituted selenoureas can be similarly prepared from the corresponding carbodiimides by reaction with hydrogen chloride followed by treatment with lithium aluminum dihydrogen selenide (Scheme 17) . This procedure avoids many of the problems associated with direct addition of hydrogen selenide.

RN C NR'

i

Cl RHN C NR'

ii

Se RHN C NHR'

56–93% i. HCl, rt, 4 h; ii. LiAlHSeH, 0 °C, 2 h

Scheme 17

Reactions of primary or secondary amines with triethyl orthoformate and selenium at elevated temperatures in a sealed vessel directly affords the corresponding selenoureas (Equation (29)) . Both cyclic and acyclic selenoureas can be prepared using this method.

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group R NH

R N

i

+

(EtO)3CH

Se 39–95%

NH R

585

N R

ð29Þ

R = Me, Et, But i. Se, 180–190 °, 8 h, sealed vessel

Simple tetra-substituted selenoureas can be prepared by reaction of sodium trichloroacetate (or chloroform) with secondary amines and elemental selenium in HMPA in the presence of sodium hydride (Equation (30)) . Bis-(N,N-dialkylselenocarbamoyl) triselenides are also formed in the reaction, but the amount of these formed can be controlled by varying the temperature and the amount of amine used in the reaction (cf. Section 6.19.3.5, Equation (25)). R1 N R2

NaH, HMPA Cl3CCO2Na

+

R1R2NH

Se

+ Se

N R1 R2

20–65% 1 2 R , R = Et 1 R , R2 = Bun

ð30Þ

1 2 R , R = –(CH2)5–

Since 1994, three selenating agents have been used for the preparation of simple acyclic selenoureas. Bis-trimethylsilylselenide reacts with N,N,N0 ,N0 -tetramethylurea in the presence of boron trifluoride etherate to afford the corresponding selenourea in good yield (Equation (31)) . Monoselenophosphate reacts with cyanoguanidine to afford the corresponding selenocarbonyl compound in excellent yield (Equation (32)) . A selenium analog of the widely used sulfurbased Lawesson reagent converts N,N0 -diethylurea to the corresponding selenourea in modest yield, however, the reaction was not successful in the case of N,N0 -diphenylurea . (Me3Si)2Se, BF3·OEt2

O Me2N

Se Me2N

NMe2

ð31Þ

NMe2

64% H2PO4– H MeOH, H2O, H2PO3Se–

NH H H 2N C N C N

N H2N C

H Se H N C NH2

ð32Þ

94%

Hydroxyimidoyl chlorides can be converted to selenoureas in moderate yield via intermediate nitrile oxides 23 and isoselenocyanate intermediates (Scheme 18) . OH N Cl

C N O–

i

CH3

CH3 23 Se

i. Et3N, THF, 25 °C; ii. 0 °C, THF, R

H N CH3

H N Se

R1

NH2

R1NH2 46–78%

Scheme 18

ii

N C Se CH3

586

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group

A number of aromatic acyl selenoureidonitriles and esters have been prepared by reaction of the corresponding amines with an acyl isoselenocyanate (Equation (33)) . These compounds can be readily cyclized to the corresponding fused seleniumcontaining heterocycles . R

R

O + Ar

NH2

S

N C Se

72–96%

S

Se O H N C N C Ar H

ð33Þ

R = CN, CO2Et

Reactions of in situ-generated acyl isoselenocyanates with aniline derivatives afford N-acyl-selenoureas in good yield (Scheme 19) . Aliphatic amines react similarly . Related reactions also occur with N-phenylimidoyl isoselenocyanates (Scheme 20) and N-benzylbenzimidoyl isoselenocyanates . Primary amines can also be used in the latter reactions, but significantly lower yields were obtained using ammonia.

O Ar C Cl

O Ar C N C Se

Acetone KSeCN

Ar'NH2 71–83%

Se O Ar C NH NHAr'

Scheme 19

O Ar

N H

Ph

N

SOCl2 Ar

Ph Cl

i >98% HN Ar

Ph R2NH

N

R2N

Se

74–97% Ar

N

Ph N C Se

i. KSeCN, acetone R = alkyl, aryl, H

Scheme 20

Reaction of isonitriles with amines in the presence of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) provides a convenient preparation of selenoureas, which can be readily converted by oxygen to the corresponding carbodiimides (Equation (34)) . +

R N C–

R1NH2

i

Se H H R N C N R1

ii

RN C NR1

ð34Þ

i. Se, DBU, reflux, 1 h; ii. O2, reflux

Similarly 75Se-labeled dicyclohexylselenourea has been prepared in 90% radiochemical yield by the reaction of cyclohexylisonitrile and cyclohexylamine in the presence of 75Se (Equation (35)) . Labeled dicyclohexylselenourea can also be prepared directly by addition of labeled hydrogen selenide to the corresponding carbodiimide (Scheme 21). The resulting labeled selenourea is a useful precursor in the preparation of 75Se-labeled selenides. A polymerbound selenourea could also be prepared from the corresponding carbodiimide (Equation (36)).

587

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group NC

75Se

NH2

75

Sen

+

N H

Benzene, reflux

ð35Þ

N H

90% radiochemical yield

75Se

+

N C N

H275Se

N H

N H

NHBOC i, ii, iii i.Br

CO2Et +–

ii. Bun4N iii. MeI

OH

CO2Et Me

75Se

NHBOC

Scheme 21

75Se

N C N

+

ð36Þ

H275Se

N H

N H

A novel approach to the preparation of heterocyclic selenoureas involves direct reaction of stabilized cyclic carbenes with elemental selenium. The intermediate carbene 24 can be prepared by reaction of 2,20 -bipyridine with a triphenylarsonium salt, followed by bromide exchange and base treatment. The resulting carbene is stable for several hours at
30  C, but can be trapped by elemental selenium affording the selenourea in high yield (Scheme 22). This selenourea can be directly prepared in 87% yield in a ‘‘one-pot’’ reaction without isolation of the carbene . The reaction of other stabilized carbenes with selenium also afford selenoureas (Equation (37)) .

CH3CN, reflux

+

N N

+ Ph3As

Bu4NBr

OTf

OTf

–Ph3 As

N

N

+

+

H

H

N + N 2OTf

–

Br

H KOtBu, –30 °C, THF

Se N

N

N

87%

N

Se 24

Scheme 22

Ph N N Ph

Ph Se, toluene, reflux

N

N N Ph

Ph

Se

N Ph

ð37Þ

588

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group

Reaction of a series of electron-rich tetraalkylaminoethylenes with elemental selenium at elevated temperature affords the corresponding selenoureas in excellent yields, presumably via intermediate stable carbenes (Equation (38)) . Me Me N N

Se, toluene, reflux

Me N

96%

N Me

ð38Þ

Se N Me

6.19.4.2

N Me

Other Cyclic N(C¼Se)N Compounds

Traditional methods for the preparation of selenopyrimidines and selenopurines using selenourea continue to prove useful in the preparation of novel selenium analogs of biologically important compounds. Condensation of selenourea with ethyl 3-keto-hexanoate afforded propylselenouracil 25 the selenium analog of the widely used antithyroid drug 6-propyl-2-thiouracil (PTU) (Equation (39)) . O

O

Se +

OEt

H2N

H N

KOH, H2O

Se NH

NH2

ð39Þ

O 25

The 2- and 4-selenopyrimidine nucleosides have also been prepared via displacement reactions using selenourea and sodium hydrogen selenide (Schemes 23 and 24) . Details of the introduction of selenium into selenoguanosine derivatives using selenourea have also been reported . O RO

O

N

Cl RO

NH

O

i

N

O RO

Se RO

N

O

ii

N

O

X

RO

a. R = Bz, X = OBz b. R = p -Tol, X = H

NH O

X

RO

a. R = Bz, X = OBz b. R = p -Tol, X = H

X

a. R = H, X = OH b. R = H, X = H

i. SOCl2, DMF, CHCl3; ii. (NH2)2C=Se or NaHSe, MeOH or EtOH, 90 °C, N2

Scheme 23 O HN O

Cl F

i

N

N H

Cl

NH2

NH2 F

ii

F

N Cl

N

iii

F

N Se

N

N H

iv F

F NH2

NH2 HO

O

N

N

BzO v

O

N Se

Se HO

OH

N

BzO

OBz 90 °C, N2

i. POCl3; ii. aq. NH3, iii. NaHSe, n -BuOH, Ar; iv. BSTFA, MeCN, SnCl4, rt, 2 h; v. NH3, MeOH

Scheme 24

589

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group

The 2-selenoxoquinazoline derivative 26 can be conveniently prepared via cyclization of 2-isoselenocyanatobenzonitrile using hydrazine hydrate (Scheme 25) .

NaHSe, Na2CO3

CN N

N C Se

81%

CCl2

NH

NH2NH2, H2O

CN

N

72%

NH2

N H

Se

26

Scheme 25

The reaction of 5-aminoimidazole-4-carbonitrile with n-butylisoselenocyanate affords 27. Reaction with benzhydrylisoselenocyanate takes a very different course yielding the 1-selenopurine 28 (Scheme 26) . NH Bun N C Se

Bun

N

N

50 °C, 16 h Se

N H

N H

NC

N

27

H2N

N H

Se

H N

Ph Ph

Ph

50 °C, 16 h N C Se

N

Se Ph

Ph Ph

N H

N

N H

28

Scheme 26

Acyl selenoureidocarbonitrile 29, readily prepared by reaction of the corresponding nitrile with an acyl isoselenocyanate (Section 6.19.4.1, Equation (33)) can be readily cyclized to the corresponding fused selenopyrimidine 30 (Equation (40)) . It is interesting that very slight structural changes can lead to the tautomeric selenol form 31 being observed as the exclusive product of this reaction (Equation (41)). NH2

CN S

KOH, MeOH, heat N

Se O H N C N C Ph H

S

N H

29

CN S

Se O H N C N C Ph H

Se

ð40Þ

30

H2N KOH, MeOH, heat

N N

S

SeH

ð41Þ

31

The reaction of the aryl isoselenocyanate with the heterocyclic thiourea provides a convenient route to a number of interesting heterocyclic selenoureas, including the hypervalent sulfurcontaining selone 32 and -diselone 33 (Scheme 27) .

590

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group Me

Me N S S

+

N

Ar

N C Se

S

95%

N

N N

Ar = 4-CH3OC6H4

Se

N

N

S

N

Ar

N

Se

32

170 °C –Ar N C Se

–MeNCS 91%

Ar N S Se

Se Ar

Ar

N

170 °C Ar

N

S

N

N

N C Se

33

59%

Scheme 27

6.19.4.3

Telluroureas (R2N)2C¼Te

A series of stable cyclic telluroureas have been conveniently prepared in excellent yields by the reaction of the stable carbene imidazol-2-ylidenes 34 with elemental tellurium (Equation (42)) . The special stability of the 2-telluroimidazolines is probably due to the major resonance contributor 35. R1

R N

R1

N R

+

Te

THF, 0 °C

R1

R N

90–100%

R1

N R

Te

ð42Þ

R, R1= Me

34

R = Et, R1 = Me R = Pri , R1 = Me R = Mes, R1 = H R = Mes, R1 = Cl

R1

R N

R1

N R

R1 Te R1

R N – Te + N R 35

Reactions of electron-rich tetraaminoethylenes with tellurium also afford telluroureas (Equation (43)) . It is likely that this reaction and previously described preparations of telluroureas which required relatively vigorous conditions also proceeded via similar carbene intermediates. Me Me N N

Te

Me N Te

N Me

N Me

toluene, reflux 88%

ð43Þ

N Me

Another stable carbene approach to telluroureas parallels the previously described carbene route to selenoureas (cf. Section 6.9.4.1, Scheme 22). Treatment of the bromide salt 36 with base in the presence of tellurium affords the tellurourea in 87% yield (Equation (44)) .

591

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group Te

KOtBu, THF N

+

N

N

–30 °C

N

N

87%

–

ð44Þ

Te

Br

H

N

36

Up to the year 2003, no acyclic telluroureas have been reported in the literature.

6.19.5

HYPERVALENT SELENOCARBONYL COMPOUNDS OF THE TYPE Se¼C(X)X0

The reaction of 1,3-dimethyl-4-imidazolin-2-selone with molecular iodine affords a stable hypervalent selenocarbonyl compound 1,3-dimethyl-4-imidazolin-2-ylium diiodoselanide 37 characterized by a linear I
Se
I arrangement of atoms (Equation (45)) . A similar linear Br
Se
Br arrangement was noted when the same imidazolin-selone was treated with bromine . When the 1,10 -bis(3-methyl-4-imidazolin-2-selone)methane 38 was treated with iodine a linear I
I
Se structure (39) was observed in contrast to linear Br
Se
Br structures noted for other bis-halo adducts with other selenoureas (Equation (46)) . Me N

Me X N Se N X Me

CH2Cl2 Se

+

X2

N Me X = I, Br

ð45Þ

37

I2 Me

N

N

N

Se

N

Me

CH2Cl2

Me I

Se

N

N

N

I Se

38

N

Se

I

Me

ð46Þ

I

39

Hypervalent adducts of N-methylbenzothiazole-2-selone and related compounds show a fascinating variety of structural types . A ‘‘T-shaped’’ structure was noted for dibromide 40 . Aryltellurium halide adducts 41 and 42 of the same benzothiazole precursor have also been reported . Spectroscopic evidence for 1:1 selenocarbonyl–Cl2 adducts has also been reported . Br Br

S

S

Te Ph

S

Se

Se N Br Me

N Me

40

41

Se

Te

N Me

OCH3

Cl3 42

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594

Functions Containing a Selenocarbonyl or Tellurocarbonyl Group Biographical sketch

Lynn James Guziec was born in Long Beach, California; she studied at Russell Sage College, Troy, NY where she received her B.A., special honors in Chemistry, in 1979. She received her Ph.D. in 1988 from New Mexico State University under the direction of Frank Guziec, Jr. She remained as a College Professor at New Mexico State University until 1995. She has been working as an Assistant Professor at Southwestern University since 1996. In 1998 she received an M.Sc. in Biological Sciences from the University of Warwick, UK. Her interests include heterocycles, organosulfur and organoselenium compounds, as well as the synthesis of medicinal and anticancer compounds.

Frank Guziec was born in Chicago, he studied at Loyola University of Chicago where he received a B.S. (Honors) degree in 1968. He received his Ph.D. degree in 1972 at MIT under the direction of Professor J. C. Sheehan. He carried out postdoctoral work at Imperial College, London with Professor D. H. R. Barton, at MIT with H. G. Khorana, and at Wesleyan University with M. Tishler. He has served on the Chemistry faculties of Tufts University, New Mexico State University and is currently Dishman Professor of Science at Southwestern University. He carried out sabbatical research in the Pharmaceutical Sciences Department at DeMontfort University, Leicester, UK with L. Patterson under a Fulbright Fellowship and with H. Hiemstra at the University of Amsterdam. His scientific interests include the chemistry of organoselenium compounds, extrusion reactions, functionalizing deamination reactions, and sterically hindered molecules. Collaborating with his wife Lynn Guziec he is also involved in the design and synthesis of anticancer compounds.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 573–594

6.20 Functions Containing an Iminocarbonyl Group and at Least One Halogen; Also One Chalcogen and No Halogen T. L. GILCHRIST University of Liverpool, Liverpool, UK 6.20.1 INTRODUCTION 6.20.2 FUNCTIONS CONTAINING AT LEAST ONE HALOGEN 6.20.2.1 Iminocarbonyl Compounds with Two Similar Halogen Functions 6.20.2.1.1 Carbonimidic difluorides, F2C¼NR 6.20.2.1.2 Carbonimidic dichlorides, Cl2C¼NR 6.20.2.1.3 Carbonimidic dibromides, Br2C¼NR 6.20.2.2 Iminocarbonyl Compounds with Two Dissimilar Halogen Functions 6.20.2.3 Iminocarbonyl Halides with One Halogen and One Other Heteroatom Function 6.20.2.3.1 Iminocarbonyl chlorides with one other heteroatom function 6.20.3 FUNCTIONS CONTAINING AT LEAST ONE CHALCOGEN (AND NO HALOGENS) 6.20.3.1 Iminocarbonyl Compounds with Two Similar Chalcogen Functions 6.20.3.1.1 Iminocarbonyl compounds with two oxygen functions 6.20.3.1.2 Iminocarbonyl compounds with two sulfur functions 6.20.3.1.3 Iminocarbonyl compounds with two selenium functions 6.20.3.2 Iminocarbonyl Compounds with Two Dissimilar Chalcogen Functions 6.20.3.2.1 Iminocarbonyl compounds with one oxygen and one sulfur function 6.20.3.2.2 Iminocarbonyl compounds with one oxygen or sulfur and one selenium function 6.20.3.3 Iminocarbonyl Compounds with One Chalcogen and One Other Heteroatom Function 6.20.3.3.1 Iminocarbonyl compounds with one oxygen and one nitrogen function 6.20.3.3.2 Iminocarbonyl compounds with one sulfur and one nitrogen function 6.20.3.3.3 Iminocarbonyl compounds with one selenium and one other heteroatom function

6.20.1

595 596 596 596 597 597 598 598 598 599 599 599 599 600 600 600 601 601 601 602 602

INTRODUCTION

This chapter covers methods of synthesis of a wide range of iminocarbonyl compounds that have two heteroatoms attached to the carbon of the iminocarbonyl function. Only a few new methods for the preparation of these compounds have been described since the earlier review (chapter 6.20 in ). The new methods, and new examples of the more important general methods, are described here. 595

596 6.20.2

Functions Containing an Iminocarbonyl Group and at Least One Halogen FUNCTIONS CONTAINING AT LEAST ONE HALOGEN

6.20.2.1

Iminocarbonyl Compounds with Two Similar Halogen Functions

Compounds having the formula XYC¼NR (X,Y = halogen) are named as carbonimidic dihalides under the IUPAC nomenclature system. They are also commonly referred to as isocyanide dihalides or as iminocarbonyl dihalides in the literature. The most detailed review of methods of preparation of carbonimidic dihalides is by Ku¨hle . The majority of compounds of this type bear two similar halogen functions. The most common compounds of this class are carbonimidic dichlorides (X,Y = Cl) and several have been found as natural products in marine organisms; these include examples that have been described since the publication of COFGT (1995) . The general methods available for compounds in this class remain those described in chapter 60.20.1.1 in ; new examples of these methods and a few new specific methods are described in the following sections. There are no new reports of methods for dihaloiminium cations or for carbonimidic diiodides. 6.20.2.1.1

Carbonimidic difluorides, F2C¼NR

Methods for the preparation of carboimidic difluorides are those described in chapter 60.20.1.1.1 in . The most general of these methods are summarized briefly in Scheme 1. Further examples of the conversion of carbonimidic dichlorides into carbonimidic difluorides (method B) have been described . A further illustration of method D is the preparation of perfluorinated carbonimidic difluorides by the dechlorination of the perhaloalkane 1 with a catalytic amount of trimethyltin chloride (Equation (1)) .

F F

KF or base NHR A

F

Cl

F NR B

Cl

F NR F

F2

+ NR

C F Cl

N(Cl)R D

F

Scheme 1

F

Cl

Me3SnCl, 25 °C

F

Quant.

F

N

Cl F

N N(CF3)2

N(CF3)2

ð1Þ

1

A new method for the preparation of N-(trifluoromethyl)carbonimidic difluoride 2 is the thermal decomposition of potassium perflluorodimethylaminoacetate (Equation (2)); compound 2 was obtained as the principal product, but it was not completely separated from by-products . F K O2C

F

CF3 N CF3

270–280 °C

F

45%

F

N CF3 2

ð2Þ

Functions Containing an Iminocarbonyl Group and at Least One Halogen 6.20.2.1.2

597

Carbonimidic dichlorides, Cl2C¼NR

The most general methods for the preparation of carbonimidic dichlorides are summarized in Scheme 2. All these methods were described in chapter 60.20.1.1.2 in . A few publications that include some experimental detail have appeared with additional examples of some of these methods. Thus, some new N-arylcarbonimidic dichlorides have been prepared by the reaction of aryl isothiocyanates with chlorine (method A) . A new exchange reaction has been used to prepare 2-biphenylylcarbonimidic dichloride from the corresponding dibromide (Equation (3)) . Cl2 S

NR A Cl2 or SO2Cl2 NR B

Cl NR

SO2Cl2, SOCl2 O

Cl

(R = aryl ) NHR C RCl

Cl

N D

Scheme 2

Br

Cl

Ph

SO2Cl2, SnCl4

N Br

6.20.2.1.3

Ph N

ð3Þ

Cl

Carbonimidic dibromides, Br2C¼NR

The addition of bromine to isocyanides (Equation (4)) is the most general method for the preparation of carbonimidic dibromides. A wide range of isocyanides has been used and several new examples have been reported . The reaction can be used as a method of protection of sensitive isocyanide functions since it can be reversed by reduction with triethyl phosphite or magnesium . Br Br2

+

NR

ð4Þ

NR Br

The dibromooxime 3 has been prepared from glyoxylic acid aldoxime and bromine as described in chapter 60.20.1.1.3 in . The oxime 3 is important as a source of the nitrile oxide 4, a useful 1,3-dipole (Scheme 3). The reaction sequence is often carried out without isolation of the intermediate dibromooxime 3 but there is also a description of a further experimental procedure for its isolation . An analogous procedure has been used to generate carbonimidic dibromides (without HO2C

Br N OH

Br

+ – N O

Br

N OH 3

Scheme 3

4

598

Functions Containing an Iminocarbonyl Group and at Least One Halogen

isolation) from the benzylhydrazone and the phenylhydrazone of glyoxylic acid.

6.20.2.2

Iminocarbonyl Compounds with Two Dissimilar Halogen Functions

No further advances in this area have occurred since the publication of chapter 6.20.1.2 in .

6.20.2.3

Iminocarbonyl Halides with One Halogen and One Other Heteroatom Function

There have been very few advances since the publication of chapter 6.20.1.3 in . The most general method of preparation of compounds of this type is the selective displacement of one halogen from the appropriate iminocarbonyl dihalides, the main difficulty being in limiting the displacement to a single halogen. Other approaches that have some generality are addition reactions to isocyano groups and (for chloro compounds) chlorination of precursors such as isothiocyanates, ureas, and thioureas. New examples of these reactions are mainly restricted to iminocarbonyl chlorides with a nitrogen function.

6.20.2.3.1

Iminocarbonyl chlorides with one other heteroatom function

The electrophilic addition of sulfenyl chlorides to isocyanides is a known method for the preparation of iminocarbonyl chlorides with a sulfur function. A specific extension of this method to a nitrogen species is the addition of N-chlorobenzotriazole to isocyanides, which leads to mixtures of N-1 substituted and N-2 substituted benzotriazoles 5 and 6 (Equation (5)) . The method appears to have the potential of extension to other N-halo compounds.

N N

N N

NR

+

N

NR

Cl

70–93%

Cl

ð5Þ

N

NR

R = Ar, Bn, TsCH2, BtCH2

N

N

N

+

Cl

5

6

Carbonimidic chlorides that bear a nitrogen function have proved to be useful intermediates in various heterocyclic syntheses. Two recent examples that represent applications of known methods are illustrated in Scheme 4. A synthesis of 2,4-diaminoquinazolines makes use of X

X NMe2

Et2N

PCl5

NH O

Et2N

Me2NCN, TiCl4

N

X N

Cl

N

7

NEt2

Cl NMe2 Cl Cl N NH2

CN

8 N N

CN Cl NMe2

HCl (g)

Cl

N N

N NMe2 9

Scheme 4

599

Functions Containing an Iminocarbonyl Group and at Least One Halogen

the imidoyl chlorides 7 as key intermediates; they are prepared from N-aryl-N0 ,N0 -diethylureas by reaction with phosphorus pentachloride . The reaction of primary amines with dichlorodimethyliminium chloride 8 is a known and efficient method for the preparation of dimethylamino substituted imidoyl chlorides and this method has been used in a synthesis of the pyrrolotriazine 9 .

6.20.3

FUNCTIONS CONTAINING AT LEAST ONE CHALCOGEN (AND NO HALOGENS)

6.20.3.1

Iminocarbonyl Compounds with Two Similar Chalcogen Functions

6.20.3.1.1

Iminocarbonyl compounds with two oxygen functions

A general method for the preparation of compounds of this class (carbonimidic diesters) is the displacement of chloride from carbonimidic dichlorides by an excess of an alcohol or a phenol under basic conditions. A recent variation of this method that has been used to prepare the iminodioxolenes 10 is the cathodic reduction of diaryl-substituted 1,2-diketones in the presence of N-arylcarbonimidic dichlorides (Equation (6)) . Otherwise, the methods of preparation of these diesters are as described in chapter 6.20.2.1.1 in . Ar1

O

Cl NAr

+ Ar 2

2e

O

Ar 2

O

NAr 3

Cl

O

Ar1

3

ð6Þ

10

6.20.3.1.2

Iminocarbonyl compounds with two sulfur functions

Carbonimidic dithioesters are usually prepared most conveniently by S-alkylation of dithiocarbamate salts or esters, which are in turn readily available from the reaction of primary amino compounds with carbon disulfide. Methods involving displacement of halide are relatively less used, but new examples of such reactions include routes to the sulfones 11 (R = Me or Ph) by displacement of bromide . The sulfur(II) substituent in compounds 11 can be oxidized by MCPBA to give the bis(sulfones) 12 (Scheme 5). The oxime 14 was prepared in high yield by a double displacement reaction of the sulfone functions of compound 13 by sodium methylmercaptide (Equation (7)) .

PhO2S NOTHP

RSNa 78–85%

Br

PhO2S

MCPBA

PhO2S

NOTHP

NOTHP

RS

RO2S 11

12

Scheme 5

O2 S

2 NaSMe

MeS

NOBn S O2 13

NOBn 92%

MeS 14

ð7Þ

600

Functions Containing an Iminocarbonyl Group and at Least One Halogen

6.20.3.1.3

Iminocarbonyl compounds with two selenium functions

There are no general methods for the preparation of this small class of compounds. An example of a preparation of an acyclic species from an isoselenocyanate is shown in Equation (8), but this method has no generality . Most of the known compounds of this class are 2-iminodiselenoles; two examples of the preparation of these compounds are shown in Scheme 6 . BuSe N

Se

Me

N

ButLi, BuI

Me

Me

ButSe Me

31%

ð8Þ

Me

Me

Me

Me

KOBut

N N Se

Se

+

Se

NPh

NPh 53%

Se

I Me

I2, NH4OH

Se

Me

Se

NMe2 Se

Me

Se

Me

PF6

NMe2

Me

Se

Me

Se

NNMe2

NH

90%

I

Scheme 6

6.20.3.2

Iminocarbonyl Compounds with Two Dissimilar Chalcogen Functions

With the exceptions of the reactions detailed below the methods for the preparation of these compounds are as described in chapter 6.20.2.2 in .

6.20.3.2.1

Iminocarbonyl compounds with one oxygen and one sulfur function

Isothiocyanates are the most commonly used starting materials for the preparation of compounds of this class; an alkoxide is added to the isothiocyanate to give a salt that is then S-alkylated. Some new examples of this method, with sodium methoxide as the nucleophile, have been described . An example of the procedure in which tributyltin oxide is used as the base is shown in Scheme 7 . The dithiazolone 15 has been prepared by a related method involving one-pot N-acylation and S-thiolation of ethyl thiocarbamate .

EtOH, (Bu3Sn)2O S

S

74%

TMS

S

ClS NH2

EtO

+

EtOTf

EtS

60%

EtO

NH

N EtO

Et3N

N TMS

S

O Cl

63%

O

S N EtO 15

Scheme 7

TMS

601

Functions Containing an Iminocarbonyl Group and at Least One Halogen

A new method for the preparation of 2-acetylimino-1,3-oxathiazoles is illustrated in Scheme 8. Reaction of the dicyano epoxide 16 with potassium thiocyanate and acetic anhydride gave the oxathioles 17; the five-membered ring is probably formed by intramolecular addition of a hydroxyl group to the CN triple bond, as shown . Ar

Ar O

SCN

Ar

S

SCN

NH

OH

NC

NC

CN

NC NC

CN

S

NC

O

NAc

42–69%

O

Ar Ac2O

16

17

Scheme 8

6.20.3.2.2

Iminocarbonyl compounds with one oxygen or sulfur and one selenium function

A few new compounds in this category have been prepared by methods analogous to those in the two preceding sections. The first 1,3-oxaselenoles 18, having structures analogous to the oxathioles 17 but with selenium in place of sulfur, were prepared by the method shown in Scheme 8 but with potassium selenocyanate as the nucleophile . 2-Phenylimino-1.3-thiaselenole 19 has been prepared in low yield by a method analogous to that in Scheme 6, from the reaction of phenyl isoselenocyanate with 1,2,3-thiadiazole (Equation (9)) . A displacement reaction analogous to that of Scheme 5 has been carried out using the sodium salt of benzeneselenol (NaSePh) to give the sulfone 20 .

N N

Se

+

KOBut

Se

12%

S

NPh

S

NPh

ð9Þ

19

Ar

PhSe

Se NAc

NC

O 18

6.20.3.3

N PhO2S

OTHP 20

Iminocarbonyl Compounds with One Chalcogen and One Other Heteroatom Function

With the exceptions described below, the general methods available for compounds in this class remain those described in chapter 60.20.2.3 in .

6.20.3.3.1

Iminocarbonyl compounds with one oxygen and one nitrogen function

Compounds of this class are commonly known as isoureas or as pseudoureas. A review of their methods of preparation and their properties has appeared . General methods for their preparation include addition of nucleophiles to the CN triple bond of cyanates or cyanamides, and addition–elimination reactions of other iminocarbonyl compounds. Two new examples of these two general approaches are shown below. The salt 21 was prepared from cyanamide by reaction with butanol and anhydrous 4-toluenesulfonic acid in anhydrous chloroform (Equation (10)) . Displacement by an amine of one phenoxy group from the activated iminocarbonate 22 gave the isourea 23 in good yield (Equation (11)) .

602

Functions Containing an Iminocarbonyl Group and at Least One Halogen H2N

BuOH, 4-TsOH anhyd. H2N

NH2 OTs

N 70%

ð10Þ

BuO 21

PhO +

NCN

NH2.HNO3

O2NO

PhO

Et3N

H N

O2NO

NCN

87%

22

6.20.3.3.2

ð11Þ

PhO 23

Iminocarbonyl compounds with one sulfur and one nitrogen function

Compounds of this type are commonly known as isothioureas. This large and mostly stable group of compounds can be prepared by a variety of methods, the most general of which is S-alkylation of thioureas. The thioureas can, in turn, be prepared by the addition of nitrogen nucleophiles to isothiocyanates. An example of this reaction sequence, through the intermediate thiourea 24 followed by S-methylation, is shown in Scheme 9 .

NH S

N

N TMS

S

N

MeI

NH TMS

N

97% (2 steps)

MeS

TMS

24

Scheme 9

Another method that is useful for isothioureas that bear an activating group on nitrogen is nucleophilic displacement from activated carbonimidic dithioesters. A new example of this method is the preparation of the iminothiazolidine ester 25 (Equation (12)) .

CO2Et

MeS NCN

+

HS

Et3N

NH2.HCl

MeS

H N

EtO2C

NCN

95%

S

ð12Þ

25

6.20.3.3.3

Iminocarbonyl compounds with one selenium and one other heteroatom function

Compounds of this type are almost entirely restricted to those with a selenium and a nitrogen function, commonly known as isoselenoureas. As with isothioureas, the most general method for the preparation of such compounds is Se-alkylation of selenoureas. An example of this approach that has been used to prepare the selenazolone 26 is shown in Equation (13) .

N

Cl NH2

Se

Cl

+ O

Pyr, 0 °C

N

29%

Se

N

ð13Þ O

26

603

Functions Containing an Iminocarbonyl Group and at Least One Halogen

A related new approach to isoselenureas makes use of isocyanides as starting materials. The addition of a lithium dialkylamide and selenium to the isocyanide gave the lithium salts 27 which were then converted into isoselenoureas 28 by Se-alkylation with iodobutane (Scheme 10) .

R1R2N Se + R1R2NLi +

NR3

NR3 LiSe 27

BuI

R1R2N NR3 BuSe 28

Scheme 10

REFERENCES 1983HOU(E4)522 1993JCS(P1)351 1994T7543

E. Ku¨hle, Methoden Org. Chem. (Houben-Weyl) 1983, E4, 522. A. M. Le Mare´chal, A. Robert, I. Leban, J. Chem. Soc., Perkin Trans. 1 1993, 351–356. K. K. Bach, H. R. Elseedi, H. M. Jensen, H. B. Nielsen, I. Thomsen, K. B. G. Torssell, Tetrahedron 1994, 50, 7543–7556. 1994TL2365 A. Guirado, A. Zapata, J. Galvez, Tetrahedron Lett. 1994, 35, 2365–2368. 1995AG(E)586 B. Krumm, A. Vij, R. J. Kirchmeier, J. M. Shreeve, H. Oberhammer, Angew. Chem., Int. Ed. Engl. 1995, 34, 586–588. 1995CC2295 K. S. Currie, G. Tennant, Chem. Commun. 1995, 2295–2296. 1995COFGT(6)601 T. L. Gilchrist, Functions containing an iminocarbonyl group and at least one halogen; also one chalcogen and no halogen, in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, O. Meth-Cohn, C. W. Rees, Eds., Elsevier, Oxford, 1995, Vol. 6, pp. 601–638. 1995LA619 A. G. Griesbeck, J. Hirt, K. Peters, E. M. Peters, H. G. Von Schnering, Liebigs Ann. Chem. 1995, 619–623. 1995RCR929 A. A. Bakibayev, V. V. Shtrykova, Russ. Chem. Rev. (Engl. Transl.) 1995, 64, 929. 1995SC3973 J. Bernat, P. Kristian, J. Imrich, D. Mazagova, J. Cernak, T. Busova, J. Lipkowski, Synth. Commun. 1995, 25, 3973–3979. 1995T3641 A. Guirado, A. Zapata, P. G. Jones, Tetrahedron 1995, 51, 3641–3654. 1996CC41 J. E. Baldwin, R. M. Adlington, I. A. O’Neil, A. T. Russell, M. L. Smith, Chem. Commun. 1996, 41–42. 1996JOC6639 L. Chen, T. R. Thompson, R. P. Hammer, G. Barany, J. Org. Chem. 1996, 61, 6639–6645. 1996S975 M. Bergemann, R. Neidlein, Synthesis 1996, 975–980. 1996T3037 J. M. Quintela, M. J. Moreira, C. Peinador, Tetrahedron 1996, 52, 3037–3048. 1996T12165 H. Maeda, N. Kambe, N. Sonoda, S. Fujiwara, T. Shin-Ike, Tetrahedron 1996, 52, 12165–12176. 1996ZOR1870 N. I. Zmitrovich, M. L. Petrov, Zh. Org. Khim. 1996, 32, 1870–1874. (Russ. J. Org. Chem. 1996, 32, 1812–1816). 1997H(45)1405 M. Oba, M. Yoshihara, K. Nishiyama, Heterocycles 1997, 45, 1405–1410. 1997H(45)1913 M. Oba, M. Yoshihara, J. Nagatsuka, K. Nishiyama, Heterocycles 1997, 45, 1913–1919. 1997JA5982 S. Kim, J. Y. Yoon, J. Am. Chem. Soc. 1997, 119, 5982–5983. 1997JHC345 R. N. Hanson, F. A. Mohamed, J. Heterocycl. Chem. 1997, 34, 345–348. 1997SC2645 J. A. C. Alves, R. A. W. Johnstone, Synth. Commun. 1997, 27, 2645–2650. 1997T12159 H. Maeda, T. Matsuya, N. Kambe, N. Sonoda, S. Fujiwara, T. Shin-Ike, Tetrahedron 1997, 53, 12159–12166. 1998CC1143 S. Kim, J. H. Cheong, Chem. Commun. 1998, 1143–1144. 1998H(48)319 W. Zielinski, A. Kudelko, E. M. Holt, Heterocycles 1998, 48, 319–328. 1999JA5940 R. A. Moss, L. A. Johnson, D. C. Merrer, G. E. Lee, J. Am. Chem. Soc. 1999, 121, 5940–5944. 1999JFC(95)161 M. Nishida, H. Fukaya, E. Hayashi, T. Abe, J. Fluorine Chem. 1999, 95, 161–165. 1999JNP1339 J. Tanaka, T. Higa, J. Nat. Prod. 1999, 62, 1339–1340. 1999TL2605 F. Foti, G. Grassi, F. Risitano, Tetrahedron Lett. 1999, 40, 2605–2606. 2000CEJ1153 A. Chesney, M. R. Bryce, S. Yoshida, I. F. Perepichka, Chem., Eur. J. 2000, 6, 1153–1159. 2000HCA287 M. Bertinaria, G. Sorba, C. Medana, C. Cena, M. Adami, G. Morini, C. Pozzoli, G. Coruzzi, A. Gasco, Helv. Chim. Acta 2000, 83, 287–299. 2000SL33 T. Tanaka, T. Azuma, X. Fang, S. Uchida, C. Iwata, T. Ishida, Y. In, N. Maezaki, Synlett 2000, 33–36. 2001JFC(109)123 V. A. Petrov, J. Fluorine Chem. 2001, 109, 123–128. 2001JNP111 M. Musman, J. Tanaka, T. Higa, J. Nat. Prod. 2001, 64, 111–113. 2001JNP939 S. Kehraus, G. M. Konig, A. D. Wright, J. Nat. Prod. 2001, 64, 939–941. 2001JOC2854 A. R. Katritzky, B. Rogovoy, C. Klein, H. Insuasty, V. Vvedensky, B. Insuasty, J. Org. Chem. 2001, 66, 2854–2857. 2002S195 M. Koketsu, F. Nada, H. Ishihara, Synthesis 2002, 195–198.

604

Functions Containing an Iminocarbonyl Group and at Least One Halogen Biographical sketch

Tom Gilchrist was born in York, England and studied chemistry at King’s College London, where he obtained his Ph.D. under the supervision of Charles Rees. He taught for many years at Liverpool University and retired from his post as Reader in 2002. He has published extensively on heterocyclic chemistry, with special interests in small ring compounds and cycloaddition reactions. He was a volume editor for COFGT (1995), and has also edited several volumes of Progress in Heterocyclic Chemistry with Gordon Gribble. He is joint editor, with Dick Storr, of Volume 13 of Science of Synthesis. Among his other publications is a textbook, Heterocyclic Chemistry.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 595–604

6.21 Functions Containing an Iminocarbonyl Group and Any Elements Other Than a Halogen or Chalcogen F. S´CZEWSKI Medical University of Gdan´sk, Gdan´sk, Poland 6.21.1 IMINOCARBONYL DERIVATIVES CONTAINING AT LEAST ONE NITROGEN FUNCTION (AND NO HALOGEN OR CHALCOGEN FUNCTIONS) 6.21.1.1 Iminocarbonyl Derivatives with Two Nitrogen Functions 6.21.1.1.1 N-Unsubstituted iminocarbonyl derivatives 6.21.1.1.2 N-Alkyl iminocarbonyl derivatives 6.21.1.1.3 N-Alkenyliminocarbonyl derivatives 6.21.1.1.4 N-Aryliminocarbonyl derivatives 6.21.1.1.5 N-Alkynyliminocarbonyl derivatives 6.21.1.1.6 N-Acyliminocarbonyl derivatives 6.21.1.1.7 N-Cyanoiminocarbonyl derivatives 6.21.1.1.8 N-Haloiminocarbonyl derivatives 6.21.1.1.9 N-Chalcogenoiminocarbonyl derivatives 6.21.1.1.10 N-Aminoiminocarbonyl derivatives 6.21.1.1.11 N
P, N
As, N
Sb, and N
Bi iminocarbonyl derivatives 6.21.1.1.12 N
Si, N
Ge, and N
B iminocarbonyl derivatives 6.21.1.2 Iminocarbonyl Derivatives with One Nitrogen and One P, As, Sb, or Bi Function 6.21.1.2.1 N-Alkylimino derivatives with one P or As function 6.21.1.2.2 N-Arylimino derivatives with one P function 6.21.1.2.3 N-Acylimino derivatives with one P function 6.21.1.2.4 N-Haloiminocarbonyl derivatives with one P function 6.21.1.2.5 Hydrazono derivatives with one P function 6.21.1.2.6 Diazonium derivatives with one P function 6.21.1.2.7 N,N-Dialkyliminium derivatives with one P function 6.21.1.3 Iminocarbonyl Derivatives with One Nitrogen and One Metalloid Function 6.21.1.3.1 Silicon derivatives 6.21.1.3.2 Boron derivatives 6.21.1.4 Iminocarbonyl Derivatives with One Nitrogen and One Metal Function 6.21.1.4.1 Main metal derivatives 6.21.1.4.2 Transition metal derivatives 6.21.2 IMINOCARBONYL DERIVATIVES CONTAINING AT LEAST ONE P, As, Sb, OR Bi FUNCTION (AND NO HALOGEN, CHALCOGEN, OR NITROGEN FUNCTIONS) 6.21.2.1 Iminocarbonyl Derivatives with One P, As, Sb, or Bi Function and One P, As, Sb, or Bi Function 6.21.2.1.1 Bis(phosphino)iminocarbonyl derivatives 6.21.2.1.2 Bis(phosphinyl)iminocarbonyl derivatives 6.21.2.1.3 Iminocarbonyl derivatives with P function and one P, As, Sb, or Bi function

605

606 606 607 617 620 620 622 623 625 626 627 630 632 638 639 639 640 640 641 641 641 642 644 644 645 645 645 645 647 647 647 649 650

606

Functions Containing an Iminocarbonyl Group

6.21.2.1.4 Iminocarbonyl derivatives with one As, Sb, or Bi function and another As, Sb, or Bi function 6.21.2.2 Iminocarbonyl Derivatives with One P, As, Sb, or Bi Function and One Si, Ge, or B Function 6.21.2.2.1 Iminocarbonyl derivatives with one P function and one Si, Ge, or B function 6.21.2.2.2 Iminocarbonyl derivatives with one As, Sb, or Bi function and one Si, Ge, or B function 6.21.2.3 Iminocarbonyl Derivatives with One P, As, Sb, and Bi Function and One Metal Function 6.21.2.3.1 Iminocarbonyl derivatives with one P function and one metal function 6.21.2.3.2 Iminocarbonyl derivatives with one As, Sb, and Bi function and one metal function 6.21.2.3.3 N-Unsubstituted iminocarbonyl derivatives 6.21.2.3.4 N-Alkyl- and N-aryliminocarbonyl derivatives 6.21.2.3.5 N-Haloiminocarbonyl derivatives 6.21.2.3.6 N-Aminoiminocarbonyl (diazomethane) derivatives 6.21.2.3.7 N-Silyliminocarbonyl derivatives 6.21.2.4 Iminocarbonyl Derivatives with One Metalloid Function and One Metal Function 6.21.2.4.1 N-Alkyl- and N-aryliminocarbonyl derivatives 6.21.2.4.2 N-Aminoiminocarbonyl (diazomethane) derivatives 6.21.3 IMINOCARBONYL DERIVATIVES CONTAINING TWO METAL FUNCTIONS

6.21.1

650 650 650 651 652 652 653 653 653 654 654 654 655 655 655 655

IMINOCARBONYL DERIVATIVES CONTAINING AT LEAST ONE NITROGEN FUNCTION (AND NO HALOGEN OR CHALCOGEN FUNCTIONS)

6.21.1.1

Iminocarbonyl Derivatives with Two Nitrogen Functions

Iminocarbonyl derivatives (guanidines) can be obtained according to the routes depicted in Scheme 1. The following sections are ordered by type of substituents on the imino N2-atom.

NR2R3

MeI (or Me2SO4) or COCl2 or peracid

S NR4R5

X X = SMe, Cl, SO3H

NR2R3 + NR4R5

1

2

NH3, Alk-NH2

R1 N

NHR3

R Hal

NR4R5

O X = OMe, Cl, Cl2PO2

NR4R5

3

R1NH2

R1 N

2

NR2R3

MeI or COCl2 or POCl3

NR2R3

i. R2R3NH ii. R4R5NH

R1 N

Cl

NR4R5

4

Cl 6

5

R4R5NH

R4R5NH

R2 N C N R3

R1 N C N R3

7

8

Scheme 1

607

Functions Containing an Iminocarbonyl Group 6.21.1.1.1

N-Unsubstituted iminocarbonyl derivatives

Most methods for the preparation of N-unsubstituted iminocarbonyl derivatives are based on the reaction of primary or secondary amines with electrophilic precursors of the guanidine moiety. The guanylating precursor can be generated from various functions. Thiouronium salts of type 2 are generated by reacting thioureas 1 with trialkyl oxonium salts, alkyl halides, chlorinating agents, or peracids. Similarly, strong alkylating or chlorinating agents are also used for generation of electrophilic imino N2 centers from ureas 3. Compounds of type 2 react with amines in the classic reaction known as the Rathke guanidine synthesis. The direct reaction of 1-alkyl thiourea derivatives 1 with ammonia in the presence of zinc(II) or lead(II) salts gives rise to the formation of N-unsubstituted iminocarbonyl derivatives. Alternatively, 1,3-dialkyl guanidines can be prepared from activated carbamate-protected 1-alkyl urea and alkylamines in the presence of water-soluble carbodiimide followed by deprotection. Analogously, 1,3-di-t-butoxycarbonyl-thiourea is converted to 1-alkyl guanidines. Carboxamidines of type 2 bearing heteroaromatic leaving group (X = pyrazol-1-yl) and especially those N,N1-bisurethane protected (R1 = t-BOC or PhCH2OCO) are able to react with weak nucleophiles such as aromatic amines .

(i) N-Unsubstituted iminocarbonyl derivatives from thioureas Usually, the formation of guanidines from thioureas is achieved by application of coupling reagents such as mercury(II) salts, diisopropyl carbodiimide (DIC), 1-(3-dimethylaminopropyl)3-ethyl carbodiimide (EDCI) or Mukaiyama’s reagent leading to the intermediate formation of activated thiourea or carbodiimides. The following sections are ordered by type of the coupling reagent. Moreover, due to recent developments in the solid-phase synthesis, the solution-phase and solid-phase protocols will be discussed separately. (a) N-Unsubstituted iminocarbonyl derivatives from thioureas using mercury(II) salt as coupling reagent. Solution-phase methods. In 1993 Kim and co-workers reported a facile synthesis of bis(t-BOC)-protected guanidines of type 10 from thiourea 9 R2,R4 = H, R3,R5 = t-BOC promoted by HgCl2 . This method followed by deprotection with TFA offers an efficient synthesis of terminal guanidines (Equation (1)). R1R2NH

HgCl2

S

BOCN=C=NBOC BOCHN

NHBOC 9 H+

NBOC R1R2N

ð1Þ

NH R1R2N

NHBOC

NH2

10

A synthetic method for internal guanidines has also been developed, employing as the key step a nucleophilic substitution of bis(t-BOC)-protected terminal guanidines 10 . The second substituent, R2, was introduced as an electrophile (formation of 11), and t-BOC-deprotection completed the synthesis of internal guanidines 12 (Equation (2)). An analogous phase-transfer-catalyzed alkylation of 10 has also occurred regioselectively at one of the carbamate nitrogens and the reaction proved to be tolerant to a wide range of functional groups on the guanidine including esters, amines, ketones, alcohols, and alkenes . N-t-BOC R1R2N

N-t-BOC H 10

N-t-BOC

i or ii R1R2N

NH

TFA

N-t-BOC R3 11

R1, R2 = H, alkyl; R3 = alkyl, Bn; 50–95% i. NaH; ii. R3X, DMF, 0 °C to rt ii. R3X, Bu4N+ I–, KOH, DCM/H2O, rt, 4 h

R1R2N

NHR3 12

ð2Þ

608

Functions Containing an Iminocarbonyl Group

HgCl2-promoted guanylation was further studied with variously substituted thioureas 13 and the scope and limitations were presented by Ko and co-workers . The process was found to be effective with thioureas containing at least one activating group. Such N-conjugated groups include N-carbonyl (acyl, alkoxycarbonyl, carbamoyl), N-cyano, N-sulfonyl, and N-aryl substituents (Equation (3)). S 1

R HN

NX

i 1

NHX

NR2R3

R HN

13

ð3Þ R1 = cyclohexyl, p-nitrophenyl; X = COR4 ; CN, SO2R4 R2R3NH = tetrahydroisoquinoline, aniline, p-methoxyaniline; 41–95% i. R2R3NH, HgCl2, Et3N, DMF, rt

A nickel-boride-promoted guanylation of amines with N,N0 -bis(t-BOC)thiourea 13 has also been described . Solid-phase methods. A convenient solid-phase synthesis of ribonucleic guanidines 14 including abstraction of the sulfur atom from fluorenylmethoxycarbonyl (Fmoc)-protected thiourea by Hg2+ was described (Scheme 2).

O NH H2N O

LCAA-CPG

H N

O

N

O

NHMMTr

U

O

+ OTBs

TBsO

HgCl2, DMF, rt

HN

O

S

Hunig's base

NHFmoc U

NHMMTr O O

TBsO

HN

NFmoc HN O

LCAA-CPG

H N

O

NH N

O

OTBs

O 14 LCAA-CPG = long chain alkylamine-controlled pore glass (solid support) U = uracyl

Scheme 2

Mercury(II) oxide proved to be a coupling reagent capable of activating the thiourea sulfur fragment for substitution without elimination leading to the intermediate carbidiimides . Resin-bound thiourea 15 bearing two substituents at one of the nitrogen atoms reacted with ammonia and primary or secondary amines in the presence of HgO. The cleavage with 10% TFA in CH2Cl2 yielded guanidines of type 16 in the form of trifluoroacetate salts (Scheme 3).

609

Functions Containing an Iminocarbonyl Group NHR2

S N

O

N

NHR1

i. NaH, DMF

N

O

N

NR1

2

ii. R NCS, 2 h, rt Cl

Cl 15 R3N

R3NH2, MeCN

N

O

HgO, 12 h, 45 °C

N

NHR2 NR1

NR3 TFA, DCM

R1HN

NHR2

5 min, rt

Cl

16

R1 = alkyl, alkenyl, benzyl; R2 = alkyl, aryl; R3 = H, alkyl

Scheme 3

(b) N-Unsubstituted iminocarbonyl derivatives from thioureas using carbodiimide as coupling reagent. Solution-phase methods. Following the procedure elaborated by Poss and co-workers the water-soluble carbodiimide EDCI hydrochloride) was used for the synthesis of guanidinium derivatives 18 starting from carbamoyl isothiocyanates . The carbamoyl thiourea 17 obtained from ethoxycarbonyl isothiocyanate and hindered amines was coupled to a second amine in the presence of EDCI, forming 1,3-disubstituted and 1,1,3-trisubstituted guanidines through either stepwise or one-pot synthesis. The deprotection of the products was carried out using Me3SiBr under reflux in DMF followed by protonation with methanol, without cleaving of the functional groups (Scheme 4).

O Et

O

N

C

S

R1R2NH

S

Et DCM, THF

R3R4NH NR1 2

O

R

EDCl, Et3N, DCM

17

NR1R2

O Et

O

N

i, ii

NR3R4

72–79%

+ H2N

NR1R2 NR3R4

X

–

18

i. Me3SiBr, DMF, reflux; ii. Methanol

Scheme 4

Solid-phase methods. A practical solid-phase synthesis that uses Rink amide resin as an amine component in reacting with aromatic isothiocyanates and aliphatic amines to give 1,3-disubstituted guanidine of type 22 was described . The commercial Rink amide resin 19 was deprotected with 25% piperidine/DMF, and then treated with an isothiocyanate to give the resin-bound thiourea 20, which, in turn, was subjected to guanylation with an amine in the presence of DIC and Hu¨nig base (DIPEA) to give the resin-bound guanidine 21. The disubstituted guanidine 22 was cleaved off under mild Rink resin cleavage conditions (Scheme 5). A series of diverse guanidine compounds 25 (Scheme 6) were obtained based on a traceless linker approach to the solid-phase synthesis, utilizing resin-bound acyl isothiocyanate 23 . This precursor undergoes addition reactions with a variety of amines to form

610

Functions Containing an Iminocarbonyl Group S

i, ii NHFmoc 19

iii NHR1

N H 20 NR2R3

NR2R3

iv

NR1

N H

NR1

H2N 22

21

i. 25% Piperidine, DMF; ii. R1NCS, DCM, rt, 8 h; iii. R R NH, DIC, DIPEA, CHCl3, 50 °C, 2 days; iv. 25% TFA, DCM, rt, 1 h 2 3

Scheme 5

COOH

i. (COCl)2, DMF

O

ii. Bu4t N+ NCS–

NCS 23

O

R1NH2

NHR1

DMF

O

iii

NHR1

HN C

HN C NR2R3

S 24 NR2R3

iv

NHR1

HN 25

iii. R2R3NH, EDC, DIPEA, CHCl3 or DMF; iv. TFA, CHCl3, MeOH, 45–60 °C, 24–72 h

Scheme 6

the corresponding acyl thioureas 24. In the second step, a resin-bound guanidine formation is promoted through desulfurization with DIC. Cleavage of acyl guanidine is affected by treatment with TFA. A polymer-assisted synthesis (PAS) methodology to obtain guanidines 28, which combines advantages of traditional solution-phase chemistry with the application of polymeric reagents was developed as shown in Scheme 7 . Thus, N,N0 -bis(t-BOC)thiourea 9 is coupled with an amine with the use of polymer-supported carbodiimide 26. In order to remove a by-product (bis-(t-BOC)carbodiimide), PS-trisamine 27 was added as a scavenger. Further deprotection with TFA afforded terminal guanidines in very good yield. (c) N-Unsubstituted iminocarbonyl derivatives from thioureas using Mukaiyama’s reagent. Solution-phase methods. Mukaiyama’s reagent was examined as a replacement for toxic heavy metal salts to promote formation of carbodiimides from thioureas . Primary and secondary aliphatic and aromatic amines subjected to the reaction with N,N0 -bis-(t-BOC)thiourea 9 and Mukaiyama’s reagent resulted in the formation of the corresponding N,N0 -bis-(t-BOC)guanidines of type 10 in 21–91% yields (Equation (4)).

611

Functions Containing an Iminocarbonyl Group

S BOCHN

N

i.

C

N

NR1R2

NR1R2 26

iii

NHBOC

BOCHN

NBOC 87–95%

NH2

+

9

R1R2NH

N

N H

ii.

H2N

NH 28

NH2 27

iii. 25% TFA in DCM

Scheme 7

N+ Me

S t-BOCHN

NH-t-BOC

Cl

NR1R2 I– t-BOCHN

R1R2NH, DMF

9

N-t-BOC

ð4Þ

10

R1 = H, alkyl, R2 = alkyl, aryl

Solid-phase methods. An interesting strategy for generating a wide variety of guanidines 32 by solid-phase synthesis was developed by Josey and co-workers . In one-pot, thiourea was deprotonated with 2 equiv. of sodium hydride, treated with the carbonylimidazole resin 29, and then capped with t-butyl dicarbonate to afford 30. Coupling of the thiourea 30 with primary and secondary amines in the presence of Mukaiyama’s reagent afforded the desired products 31 in good yields (Scheme 8).

O O

O

i, ii N

O

N

29

S N H

ArR1NH

BOC

N H

Mukaiyama’s reagent

30

O

Pr3i SiH

NArR1

O N H

NBOC

TFA, DCM

NArR1 H2N

31

NH 32

i. NaH, thiourea, THF; ii. (BOC)2O, THF

Scheme 8

(ii) N-Unsubstituted iminocarbonyl derivatives from isothioureas Solution-phase methods. Bis-(t-BOC)-protected guanidines 34 were obtained in 77–89% yields by treatment of the commercially available N,N0 -bis-BOC-S-methyl thiourea 33 with hindered aliphatic and aromatic amines in the presence of HgCl2 . This protocol can be used for the preparation of monoaryl internal guanidines (Equation (5)).

612

Functions Containing an Iminocarbonyl Group

SMe

SMe CH2Br

t-BOCHN

N-t-BOC

t-BOCN i

33

HN

NH2 N-t-BOC

t-BOCN

i

N-t-BOC

ð5Þ

ii

34

i. KOH, TBA, toluene, 60 °C, 4 h; ii. HgCl2, Et3N, DMF, rt to 60 °C

Solid-phase methods. 1,3-Disubstituted guanidines 37 can also be prepared from isothioureas on the solid phase . The reaction of Merrifield resin-bound bis-(t-BOC)thiopseudourea 35 with alcohols in the presence of Ph3P and diisopropyl azodicarboxylate (DIAD) gave N-alkylated resin-bound intermediate 36. The Mitsunobu reaction is relevant for most primary and secondary alcohols, including benzylic and allylic alcohols. The N-alkylated products were liberated from the resin as the bis-(t-BOC)-protected guanidines by exposure of 36 to excess methanolic NH3 in DMF. Deprotection with TFA gave the corresponding N,N0 -disubstituted guanidines of type 37 (Scheme 9).

N-t-BOC S

N-t-BOC

i

NH-t-BOC

S

35

NH

ii, iii

N-t-BOC R1

R2HN

36

NHR1 37

i. R1OH, PPh3, DIAD, THF, 20 h; ii. NH3, MeOH, DMF or R2NH2, DMF; iii. TFA, DCM R1 = alkyl, bn, allyl; R2 = H, alkyl, bn; 86–100%

Scheme 9

A similar approach has been utilized for a library synthesis of the analogs of the natural dipeptide antibiotic TAN 1057A,B . 1,3-Disubstituted guanidines were synthesized using the Rink amide MBHA resin-bound methyl isothiourea 38 . Treatment with amines in DMSO afforded the corresponding guanidine derivative 39, which was cleaved from the resin with aqueous TFA to produce compounds 40 (Scheme 10).

H N

O

S

N H

NH

R1R2NH

CH3

DMSO, 70 °C

H N

O

NR1R2

N H

38

39 H N

95% TFA O H2O

40 R1 = H, alkyl; R2 = alkyl; 64–89%

Scheme 10

NH NR1R2

H2N

NH

613

Functions Containing an Iminocarbonyl Group (iii) N-Unsubstituted iminocarbonyl derivatives from 1-H-pyrazole-1-carboxamidine and related precursors

Solid-phase methods. Inspired by the previously described guanylating agent 1-H-pyrazole1-[N,N0 -bis-(t-BOC)]carboxamidine 41 , Patek and co-workers developed an acid labile linker for solid-phase synthesis of substituted guanidines . Attachment of the linker to the TentaGel–NH2 resin was accomplished using ‘‘acidic’’ coupling conditions to prevent direct displacement of pyrazole with TentaGel–NH2. Most primary and secondary aliphatic amines as well as arylamines reacted efficiently with 42, affording nearly quantitative conversion to 1,1-disubstituted guanidines of type 43 (Equation (6)). H N

O H N

O

O O

N

N

N-t-BOC

NH

i. R1R2NH, DMF, rt, 2 h R1R2N

NH2

ð6Þ

ii. TFA, DCM, H2O 43

42

4-Nitro-1-H-pyrazole-1-[N,N0 -bis-(t-BOC)]carboxamidine 44 (Figure 1) was also successfully used for guanylation of resin-bound dipeptides . S t-BOCHN

SMe NH-t-BOC

t-BOCHN

N-t-BOC 33

9 O2N

N N t-BOCHN

N NBOC

41

N t-BOCHN

N

N N N-t-BOC

44

TsO–

NH2 H2N + 45

Figure 1

A comparison of guanylating agents N,N0 -bis-BOC-thiourea 9 and agent 0 1-H-pyrazole-1-[N,N -bis(t-BOC)]carboxamidine 41 was performed on a series of primary and secondary aliphatic and aromatic amines in both solution- and solid-phase resins . Thiourea 9 performed well in solution and on solid-supported primary and secondary amines. Pyrazole 41 performed well in each case, except one aniline that failed to react. The relative reactivity of guanylating agents 9, 33, and 41 (Figure 1) was also investigated in the liquid-phase polymer-supported combinatorial synthesis of guanidines with piperazine and piperidine scaffolds . Benzotriazole methodology was further applied for the mild and efficient conversion of amines to guanidines . Benzotriazole-1-carboxamidinium tosylate 45 (Figure 1) was conveniently prepared by refluxing benzotriazole, cyanamide, and p-TsOH in 1,4-dioxane. The reaction with primary and secondary amines including aromatic amines in the presence of DIEA at room temperature afforded the corresponding guanidines in good yields.

(iv) N-Unsubstituted iminocarbonyl derivatives from urethane-protected guanidines and triflyl-diurethane-protected guanidines The new classes of urethane-protected guanylation reagents 46 , 47, and 48 as well as triflyl-protected 49 and 50 (Figure 2) have been developed and utilized for the preparation of guanidines, guanidine-containing amino acids, and peptides in both solution and solid-phase. These compounds are stable, crystalline substances that can remain stable indefinitely if refrigerated.

614

Functions Containing an Iminocarbonyl Group Triurethane-protected guanidines: NH t-BOCHN

N-t-BOC

NH-t-BOC

t-BOCHN

46

NCbz

NH-t-BOC

CbzHN

47

NHCbz 48

Triflyl-diurethane-protected guanidines: NTf t-BOCHN

NTf

NH-t-BOC

CbzHN

NHCbz

49

50

Figure 2

Solution-phase methods. A series of arginine analogs 51 was synthesized via condensation of a primary or secondary alcohol with guanylating reagents 47 and 48, under Mitsunobu conditions to produce protected alkylated guanidines (Equation (7)). A similar methodology was applied for guanylating agents 33 and 41 . COOBn

CbzHN CbzHN

COOBn

47 , PPh3, DEAD

–

(CH2)n Nt-BOC

–

THF, reflux

ð7Þ

–

(CH2)n CH2OH

t-BOCN

NH-t-BOC 51

Guanylation of aliphatic and aromatic amines with bis-(BOC)- and bis-(Cbz)-protected triflylguanidines 49 and 50 gave the condensation products in 75–100% yields . Combinatorial synthesis of N,N0 -bis-(t-BOC)-protected guanidines 52 based on the reaction of guanylating reagents 49 and 50 with soluble polymer-bound diamines has also been developed . This combinatorial liquid-phase methodology has proved to be a useful tool for constructing libraries containing diamine scaffolds (Equation (8)).

N O

NH2 (CH2)n

NO2 O

N-t-BOC NH-t-BOC NH N (CH2)n

49 MeO

ð8Þ

NO2 O

52

n = 1–3

Using the triflyl-diurethane-protected guanidines 49, and 50, guanidine-containing, biologically important molecules, e.g., guanadrel, guanoxan, guanethidine, and smirnovine, were synthesized . Moreover, guanidinoglycosides and a novel library of guanidineincorporated aminoglycoside antibiotics, guanidinopyranmycins was also synthesized using the reagent 49 . With regard to the discussion about syntheses of bis-urethane-protected guanidines, it is worth noting that a method of total deprotection of N,N0 -bis-(BOC)guanidines of type 10 has been developed . It was demonstrated that deprotection using SnCl4 proceeded smoothly in ethyl acetate at room temperature and led to the easily isolable guanidinium chlorides 53 (Equation (9)).

615

Functions Containing an Iminocarbonyl Group N-t-BOC R1R2N

NH

i, ii R1R2N

NH-t-BOC 10

.HCl

NH2 53

ð9Þ

R1, R2 = alkyl, aryl; 81–100% i. SnCl4 (4 equiv.), AcOEt, rt, 3 h; ii. MeOH

Solid-phase methods. The solid-support-linked guanylating reagent 55 consisting of a urethaneprotected triflyl guanidine attached to the resin via a carbamate linker was applied to the synthesis of guanidines from a variety of amines under mild conditions . t-BOC-guanidine was immobilized on p-nitrophenyl carbonate Wang resin to form the protected guanidine 54. Triflation of 54 resulted in the formation of resin-bound guanylating reagent 55. This reagent was used for the conversion of primary and secondary amines into resin-bound guanidines which were cleaved with TFA (Scheme 11).

N-t-BOC O

H2N

O O

O

NH2

N-t-BOC

O

NO2

HN NH2

54

i

ii, iii

O O

NH-t-BOC HN

55

NH 1 2

R RN

NH2

NSO2CF3

R1, R2 = alkyl; 33–100% i. Tf2O, Et3N, DCM, –78 °C to 0 °C; ii. R1R2NH, DCM, rt; iii. TFA, DCM

Scheme 11

Synthetic applications of diurethane-triflyl guanidines 49 and 50 were subject of a recent comprehensive review .

(v) N-Unsubstituted iminocarbonyl derivatives from di(azolyl)methanimines A mixture of di(benzotriazolyl)methanimines 56 and 57, obtained from the reaction of benzotriazole with cyanogen bromide, has been developed as a versatile guanylating reagent for the general synthesis of guanidines . The sequential condensation of two amines with 56 and 57 proved to be insensitive to electronic and steric effects and allowed for the use of a wide diversity of amines. By this method it is now possible to obtain nonprotected tri- and tetrasubstituted guanidines 58 in high yields under neutral and mild conditions using an easy purification protocol (Scheme 12). A similar approach for synthesizing guanidine compounds was reported using di(imidazol-1-yl)methanimine .

616

Functions Containing an Iminocarbonyl Group NH

NH

Bt1

1

Bt

Bt2

1

Bt

NH

R1R2NH

+

NR1R2

1

Bt

THF, rt, –BtH

57

56

NH

R3R4NH R1R2N

THF, ∆

BtH

+

NR1R2 58

N

N

Bt1 =

Bt 2 =

N

N

N

N

R1, R2 = H, alkyl, aryl; R3, R4 = H, Me, aryl

Scheme 12

(vi) N-Unsubstituted iminocarbonyl derivatives by miscellaneous methods 1,3-Disubstituted guanidines of type 59 were obtained upon solvolysis of 4,5-dihydro-2-thiazolamine hydrobromide and 5,6-dihydro-4H-1,3-thiazin-2-amine under the influence of aliphatic amines (Equation (10)) . NH

R1NH2

N (CH2)n

1

R HN

NH2

H2O

S

N H

(CH2)nSH

ð10Þ

59

n = 0, 1

R1 = Me, Et, CH2CH2OH

n = 1, 2

Amidinoureas of type 60 could be prepared by the reaction of an acyl-S-methyl thiourea with an amine followed by removal of the acyl groups (Scheme 13) . Alternatively, amidinothiourea 61 was produced by reacting dicyandiamide and sodium thiosulfate in acidic medium followed by neutralization with a base . This reaction involves three steps: (i) addition of two moles hydrogen chloride to dicyandiamide, (ii) addition of thiosulfuric acid and acidic hydrolysis, and (iii) release of the free amidinothiourea (61, gutimine) by treatment with a base (Scheme 14). CbzNCO

SMe H2N

NR1R2

O CbzHN

THF

NCbz

N H

NCbz

SMe

O CbzHN

N H

CbzHN 60

Et3N, DMF

NR1R2

O

i

NCbz

R1R2NH

N H

NH

R1 = H, alkyl; R2 = alkyl

i. H2 (60 psi), 20% Pd(OH) 2/C, 96–99%

Scheme 13

The synthesis of 11C-labeled guanidines 62 was described by Langstrom and co-workers . The conversion of the 11C-labeled cyanamide to 11C-labeled guanidines was achieved in both supercritical ammonia and aqueous ammonia solutions. The latter method gave low and

617

Functions Containing an Iminocarbonyl Group NH R1HN

+ NH2 NH

2HCl

R1HN

NHCN

R1HN

R1HN

N Cl H Cl–

+ NH2 S

H 2O

NH

Na2S2O3

N H NH

NH4OH R1HN

N NH2 H HSO– 4

NH

N H

SSO3H

S NH2

61 R1 = H, alkyl; 71–95%

Scheme 14

irreproducible yield as compared to performing the reactions in automated fluid synthesis (SFA) system. Using the SFA system designed for the use with supercritical ammonia, total radiochemical yields of 11C-labeled guanidines of 30–85% were obtained for the aromatic amines and 2–36% for the aliphatic amines (Equation (11)). RNH2

11CNBr

RNH11CN

NH3

RNH11CNH2

ð11Þ

NH R = alkyl, Ar

6.21.1.1.2

62

N-Alkyl iminocarbonyl derivatives

As shown in Scheme 1 preparation of N-alkyl guanidines may be carried out either directly from the reaction of thioureas with alkylamines in the presence of lead oxide or via S-alkyl isothiouronium salts (2, X = SMe, SEt) or isouronium salts (2, X = OMe, Cl, Cl2PO2). For the synthesis of sterically hindered pentaalkyl guanidines use of the reactive chlorformamidinium (Vilsmeier) salts is preferred. The bis-electrophilic guanidine precursor carbonimidic dichloride 6 upon reaction with 2 equiv. of the same amine or one each of two different amines gives tri-, tetra-, and pentaalkyl guanidines. Trisubstituted guanidines are also derived from the reaction of carbodiimides 8, obtained by dehydration or desulfurization of ureas or thioureas, with an amine. Reactions of alkyl cyanamides 7 with amines or amine salts give rise to the formation of N-alkylguanidines in high yields. The less common procedures involve either the reaction of complexes of mercury(II) chloride and t-butyl isocyanide with mono- and dialkylamines or lithium aluminum hydride reduction of various alkyl-substituted acyl guanidines (5, R1 = acyl) . During the 1990s, the following methods have been developed. Trichloroacetamides obtained via Overman [3,3] sigmatropic rearrangement are converted into N,N0 -dibenzyl-N0 -alkyl guanidines . The key step is the conversion of carbodiimide intermediate 63 into guanidine by rare earth triflates such as scandium or ytterbium trifluoromethane sulfonates (Scheme 15). An original sequence for solution and solid-phase synthesis of N,N0 ,N0 -trisubstituted guanidines of type 66 has been developed by Mioskowski and co-workers . The sequence involves as key intermediate a bis-electrophilic chlorothioformamidine 64 that undergoes smooth nucleophilic addition of a primary amine to afford the corresponding isothiourea. The guanidine 66 is then obtained by heating the isothiourea 65 in the presence of a primary amine in toluene (Scheme 16). In the analogous solid-phase synthesis, chloromethylpolystyrene (Merrifield resin) was used instead of benzyl chloride in the first step to give resin-bound dithiocarbonate. A library of di- and trisubstituted guanidines of type 70 was synthesized in the process termed ‘‘combinatorial synthesis on multivalent oligomeric support’’ (COSMOS) . The synthetic route consists of attaching thiourea onto the soluble tetravalent support 67, and conversion to the guanidine 68 in the presence of HgCl2 or via methyl isothiourea 69. Cleavage from the support in 20% TFA/DCM affords the guanidine 70 as the TFA salt (Scheme 17).

618

Functions Containing an Iminocarbonyl Group CCl3 CCl3CN R

HN

O i

O

HN

R

O BnNH2

CCl3

OH

HN

R

PPh3, CBr4 NHBn

N

Et3N

C

N

Bn

Sc(OTf)3 or Yb(OTf)3

R

R

N

BnNH2

63 i. Overman [3,3] sigmatropic rearrangement

Scheme 15

R1NH2

S

BnCl, CS2 R1HN

THF, rt

Bn

S

COCl2 S

Toluene, 60 °C

R1N

Bn Cl

64

R2NH2

Bn

S

Toluene, 60 °C

R1HN

R3NH2

N

Toluene, 100 °C

NR2

R1HN

65

R3 NHR2

66

Scheme 16

O HN

O (CH2)n S HN C 1 R

R1R2NH

HN

67

MeI, DMF

68

R2R3NH DMSO, 100 °C

O HN

(CH2)n NR1 HN C NR1R2

HgCl2, DMF

20% TFA/DCM

O (CH2)n SCH3 HN C NR1

H2N

69

(CH2)n NR1 HN C NR1R2 70

Scheme 17

HN R

Bn NHBn

619

Functions Containing an Iminocarbonyl Group

Another facile solid-phase synthesis of N,N0 ,N0 -substituted guanidines 75 from an immobilized amine component is depicted in Scheme 18. The resin-bound amine 71 is reacted with di-(2-pyridyl)thiocarbonate (DTP) to generate the isothiocyanate 72, which is then treated with aryl-/alkylamines to yield the corresponding resin-bound thiourea 73. Desulfurization of 73 is readily achieved by treatment with triphenylphosphine dichloride. Further reaction with aryl-/ alkylamines (formation of 74) followed by acidic cleavage with TFA yields N,N0 ,N0 -substituted guanidines 75 of excellent purity and in good yields . O

O Wang

DPT (CH2)n

O

NH2

Wang

N

71

Wang

O

C

72

S

O

O

i

(CH2)n

O

DCM, 20 °C

(CH2)n S HN

ii

Wang

NR1R2

73

TFA

(CH2)n N NR3R4

O

DCM, 20 °C

NR1R2

74 O HO

(CH2)n N

NR3R4 NR1R2

75

i. R1R2NH, N-methyl-2-pyrrolidine, 20 °C; ii. R3R4NH, Ph3P, C2Cl6, dry THF, 20 °C

Scheme 18

The solid-phase library synthesis of trisubstituted guanidines of type 78 was accomplished by dehydration of ureas 76 with p-TsCl in pyridine to give solid-supported carbodiimides 77 followed by nucleophilic addition of amines and cleavage of the solid support with TFA (Scheme 19) . O

O p-TsCl

N R1

H N

NR2

N R1

Pyridine

N

O 76

C

NR2

77

O i. R3R4NH, DMSO ii. TFA, DCM

HN R1

H N

NR2 NR3R4

78

Scheme 19

As shown in Scheme 20, trisubstituted guanidines of type 80 were synthesized on solid support via aza-Wittig coupling of alkyliminophosphorane with an aryl or alkyl isothiocyanate to generate the corresponding solid-supported carbodiimide 79, which was then reacted with a primary or secondary amine .

620

Functions Containing an Iminocarbonyl Group Rink NH

N3

i, ii

Rink NH

O

N C N

O 79

NR1R2 iii, iv

H2N

HN N

O 80 i. PhNCS, THF; ii. PPh3, THF, 25 °C; iii. R1R2NH, DMSO, 25 °C; iv. TFA, H2O, 25 °C

Scheme 20

Preparation of differentially substituted guanidinium salts 81 from phosgenium salt by sequentially introducing secondary amines of markedly different reactivity was achieved as depicted in Scheme 21 . Me + N Me

Cl Cl

Cl–

R1R2NH Et3N, DCM

Me + N Me

R3R4NH

Cl NR1R2

Et3N, DCM

Me + N Me

NR3R4

Cl–

NR1R2

81 NHR1R 2 NH(Et)2

NHR 3R 4

Pyrrolidine NH(Bn)2 Pyrrolidine NH(iPr)2 Pyrrolidine

Yield (%) 100 88 76

Scheme 21

6.21.1.1.3

N-Alkenyliminocarbonyl derivatives

Title compounds can be prepared by reacting Vilsmeier salts with ketone imines. Other methods involve the reaction of 1,1,3,3-tetramethyl guanidine with either acetylenedicarboxylate or isobutyraldehyde in the presence of catalytic amount of TsOH. No further advances have occurred in this area since publication of chapter 6.21.1.1.3 .

6.21.1.1.4

N-Aryliminocarbonyl derivatives

In general, the methods developed for syntheses of N-alkyl guanidines are also applicable to the preparation of N-aryliminocarbonyl derivatives. Thus, they can be obtained from amidinium salts 2 and urea derivatives 3, carbonimidic dichlorides 6, carbodiimides 8, and cyanamides 7 (Scheme 1) . Since then, however, several new methods for the preparation of this class of compounds have been developed.

(i) N-Aryliminocarbonyl derivatives from guanidines A straightforward synthetic approach to 6-guanidinopurines consists in the reaction of the 6-chloropurine derivatives with guanidine in DMF solution in the presence of DABCO as catalyst . Similarly, the 4-O-triisopropylphenylsulfonyl (OTPS) thymidine can be guanylated directly in the presence of t-BuOK .

621

Functions Containing an Iminocarbonyl Group (ii) N-Aryliminocarbonyl derivatives from thioureas

Ramadas and co-workers have developed several methods for direct syntheses of N-aryl-substituted guanidines 83 from N-arylthioureas 82. A rapid synthesis of N,N0 -di- and N,N0 ,N0 -trisubstituted guanidines can be achieved using copper sulfate–silica gel in the presence of an amine (Scheme 22, Method A). This method, however, suffers from disadvantages involving the unstable carbodiimide intermediate, use of costly copper salt, and the need for anhydrous conditions . Desulfurization of monoaryl and N,N0 -diarylthioureas with lac sulfur adsorbed on alumina followed by treatment with ammonia, diethylamine, or morpholine in the presence of triethanolamine provided the corresponding guanidines in 68–85% yields (Scheme 22, Method B). Hydrogen sulfide is effectively trapped by triethanolamine and, therefore, this process is bound to trigger commercial interest since pollution due to hydrogen sulfide is avoided . Oxidation of N,N0 -disubstituted thioureas using the previously unexploited reagents sodium metaperiodate and sodium chlorite in aqueous medium provides another facile and high-yielding route to N-aryl guanidines (Scheme 22, Method C) .

S R1HN

NR3R4

i, ii or iii, iv or v, vi

NHR2

R1N

82

NHR2 83

Method A: i. CuSO4, SiO2, TEA, THF; ii. R3R4NH, rt Method B: iii. Lac sulfur on alumina, triethanolamine; iv. R3R4NH, reflux Method C: v. NaIO4 or NaClO2; vi. R3R4NH, DMF–H2O, 80–85 °C R1

R2

R3

Ph Ph

Ph Ph

H CH3

Ph

Ph

CH3

Ph

Ph

C6H11

Ph Ph o -Tolyl

C2H5 Ph Ph Bn o -Tolyl C2H4OH

Ph

Ph

H

Ph

Ph

Et

Ph

Ph

Ph

C6H11

R4 H

Cond.

Yield (%)

Method

i, ii i, ii

90 78

A A

i, ii

75

A

i, ii

85

A

H

i, ii i, ii i, ii

90 80 75

A A A

H

iii, iv

85

B

Et

iii, iv

82

B

Morpholyl H

iii, iv

85

B

Morpholyl H

iii, iv

72

B

80

B

H CH3 H C2H5 C2H5

o -Tolyl

H

Morpholyl H

iii, iv

Ph

Ph

H

H

v, vi

76a, 80b

C

Ph

Ph

H

C6H11

v, vi

84a, 81b

C

a

b

C

a

b

Ph

Ph

H

Bn

v, vi

68 , 65

Ph

Ph

Et

Et

v, vi

76 , 80

C

Ph

Ph

C6H11

C6H11

v, vi

60a, 53b

C

a

NaIO4; b NaClO2.

Scheme 22

622

Functions Containing an Iminocarbonyl Group

(iii) N-Aryliminocarbonyl derivatives from isothioureas The reaction of a variety of anilines with a new N-methylguanylating agent 85 was reported to give the corresponding N-aryl guanidines 86 (Scheme 23). Formation of 85 entailed reaction of commercially available N-methyl thiourea with (BOC)2O to provide 84. Treatment of 84 with 2,4-dinitrofluorobenzene (Sanger’s reagent) furnished 85 in 86% yield .

NO2

O2N S t-BOCHN

S

Sanger’s reagent NMe-t-BOC

t-BOCN

N

i. ArNH2, Et3N NMe-t-BOC

H2N

ii. TFA

85

84

Ar NHMe

86

Scheme 23

Two solid-phase syntheses of libraries of N-aryl-substituted guanidinocarboxylic acids of type 89 were described . The first method involving trapping of solution-phase carbodiimides 87 by supported amines was used to produce N-aryl-N0 ,N0 -dialkyl derivatives 88 (Scheme 24). A limitation of this method was that the supported guanidines 88 tended to undergo an undesired intramolecular cyclization. The second solid-phase method (Scheme 25), featuring supported carbodiimides 90 and solution-phase amines was devised to prepare N,N0 -disubstituted and N,N0 ,N0 -trisubstituted guanidinocarboxylic acids 89. O S R1HN

NR2

Mukaiyama’s reagent NHR2

R1N

DCM, Et3N, 25 °C

Wang

C

(CH2)n NH2

87

84 O Wang

O

O

O

(CH2)n NHR2 HN

88

NR1

TFA, DCM

HO

(CH2)n NHR2 HN

89

NR1

25 °C, 1 h

R1= aryl, R2 = akyl; 53–96%

Scheme 24

(iv) N-Aryliminocarbonyl derivatives from carbodiimides Alkylation of the highly electron-deficient amines with N-trityl-protected carbodiimides 91 as shown in Scheme 26 leads to the formation of N,N0 -bis(aryl)guanidines 92 . The dehydration of N-trityl-N0 -arylureas to the corresponding carbodiimides 91 is achieved using the Burgess reagent.

6.21.1.1.5

N-Alkynyliminocarbonyl derivatives

The flash photolysis of phenylguanidinocyclopropenone leads to the formation of 2-(phenylethynyl)-1,1,3,3-tetramethyl guanidine as a transient intermediate which, in aqueous solution, is converted to an acyl guanidine .

623

Functions Containing an Iminocarbonyl Group R1

S O

N H

O

i O

N H

N

C

N R1

O 90

NR2R3 O

R1R2NH

O

25 °C, 10 h

N H

NR2R3 HO

TFA, DCM

N

N H

O

25 °C, 1 h

89

R1

N

R1

R2, R3 = alkyl; 56–94% i. Mukaiyama’s reagent, DCM, Et3N, 25 °C, 1 min

Scheme 25

O R1HN

NHR2

R1 = aryl, R2 = Tr

+

O + O Et3 N S N O –

DCM, 25 °C R1N

Burgess’ reagent

C

91

NHR1

i, ii, iii N

NR2

OMe

NH2

N

N 92

NH2 R1 = aryl

i. NaH, DMF; ii. 91; iii. 4N HCl, i -PrOH

Scheme 26

As shown in Scheme 27, the N-alkylideneynamines 94 can be prepared by the reaction of perchlorobutyne with tetramethyl guanidine (TMG). The trichlorovinyl group of 93 is transformed by buthyllithium and chlorosilane into a silylethinyl moiety .

6.21.1.1.6

N-Acyliminocarbonyl derivatives

Title compounds (5, R5 = acyl) are obtained by acylation of the free base of S-methyl isothiouronium salts (2; X = SMe) followed by treatment with monoalkylamines (Scheme 1). Condensation of unsubstituted or monosubstituted guanidines with acid esters gives monoacetylated products. The preparation of di- and trisubstituted guanidines can be accomplished using acid chlorides or anhydrides. Reactions of guanidines with N,N-dimethylthiocarbamoyl chloride or isothiocyanates give rise to the formation of corresponding 2-(thiocarbamoyl)guanidines. Similarly, 2-amidinoureas (5; R1 = ArNHCO) can be obtained by reacting guanidines with aryl isocyanates (ArNCO) or carbamoyl chlorides (ArNRCOCl) . The following methods have been developed since the publication of COFGT (1995).

624

Functions Containing an Iminocarbonyl Group Cl Cl

Cl

2TMG

C C C Cl C Cl

N(Me)2 C C C N C C N(Me)2 Cl

Cl

i. 2BuLi ii. ClSiMePh2

93

N(Me)2 MePh2Si

C C C C N C N(Me)2

94

Scheme 27

(i) Solution-phase methods As shown in Scheme 28 N-benzoyl thioureas can be easily converted to N-benzoyl guanidines of type 95 by HgCl2 promoted reaction with alkyl and aryl amines . N-benzoyl thioureas are also converted to the corresponding acyl guanidines using an amine in the presence of coupling reagents such as EDCI or 2-chloro-1-methylpyridinium iodide (Mukaiyama’s reagent) . Bismuth nitrate pentahydrate was also found to serve as an effective reagent for guanylation of N-benzoyl thioureas (Scheme 28) . O Ph

S N H

NHR2

O

i or ii or iii or iv NHR1

Ph R1, R2 = alkyl, aryl

N

NHR1

95

i. R2NH2, HgCl2, Et3N, DMF, 60–81% ii. EDCI, DAMP, Et3N, 30–74% iii. Mukaiyama's reagent, 75% iv. Bi(NO3)3.5H2O, DMF, 60–81%

Scheme 28

An improved procedure for the generation of 1-aroyl-S-methyl isothiourea derivatives 96 consists in the reaction of acid chloride (1 equiv.) in ether with S-methyl isothiouronium sulfate (2 equiv.) in sodium hydroxide under ice-cold conditions (Scheme 29). Subsequent condensation with aromatic and aliphatic amines gives the desired N-acyl guanidines 97 in 48–74% yields .

R1

Cl O

SMe + H2N

NH

NaOH 0–5 °C

H N

R1 O

SMe NH

96

R2NH2, Et3N Xylene, reflux

R1

N

NHR2 NH2

O

97

R1 = aryl, thienyl; R2 = alkyl, aryl

Scheme 29

(ii) Solid-phase methods N-acylation of the resin-bound S-methyl isothiourea 98 with carboxylic acid using 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP) as coupling reagent followed by displacement of the thiomethyl group with ammonia, a variety of

625

Functions Containing an Iminocarbonyl Group

primary or secondary amines or aniline resulted N-acyl-N0 -alkyl(aryl)guanidines 99 which are liberated from the resin upon exposure to TFA (Equation (12)) . H N

O O

O

i, ii, iii

SMe

R1

NH

NH2 NR2R3

N

ð12Þ 98

99

i. R1PyAOP, DIPEA, NMP; ii. R2R3NH, NMP; iii. TFA, DCM

In a similar manner, starting from amino acid immobilized on polystyrene Wang or Rink amide resin, the synthesis of N-acyl-N0 -carbamoyl guanidines can be achieved . The resin-bound pyrazole carboxamidine 100 upon deprotonation with lithium hexamethyldisilazide (LiHMDS) followed by treatment with an acyl chloride affords the resin-bound guanylating agent 101. The latter compound reacts with an amine to provide resin-bound disubstituted guanidine which is cleaved with TFA at room temperature (Scheme 30) .

Wang

H N

O O

NH N

i, ii

Wang

O

H N

N O

N

100

N

N

NH O

R1

iii, iv

2 3

R R N

O

N H

R1

101 R1 = aryl, alkyl, bn; R2, R3 = alkyl, aryl; 61–88% i. LiHMDS, THF, 0–5 °C; ii. R1COCl; iii. R2R3NH, THF; iv. TFA, DCM, 2 h

Scheme 30

6.21.1.1.7

N-Cyanoiminocarbonyl derivatives

Title compounds are most often prepared from thioureas and their derivatives. These methods include (i) the reaction of an N,N0 -disubstituted thiourea with lead cyanamide, (ii) reaction of an amine with N-cyano-N0 ,S-dimethyl isothiourea, and (iii) the reaction of an amine with dimethylcyanodithioimidocarbonate followed by treatment with alkylamine. 2-Cyanoguanidines are also obtained in high yields by reacting cyanamide (H2NCN) with carbodiimides (8; R1 = aryl, R2 = alkyl) in the presence of catalytic DIPEA (Hu¨nig base). Condensation of sodium (or lithium) dicyanamide with monoalkylammonium salts yields the corresponding monosubstituted 2-cyanoguanidines (5; R1 = CN, R2,R3 = H, R4 = alkyl) (Scheme 1) . Recently, three novel methods for preparation of 1,3-substituted cyanoguanidines 104 have been developed. One involves the reaction of commercially available diphenylcyanocarbonimidate 102 with anilines and subsequent treatment of the obtained cyano-O-phenylisourea 103 with alkylamines (Scheme 31) . Dimethyl cyanodithioiminocarbonate 105 reacts similarly .

Ph

O

O N

102

Ph

CN

ArNH2, rt, 14 h 73%

Ar

H N

O N

Ph

R1NH2, base

CN

103 R1 = alkyl, aryl; base = Et 3N, Py

Scheme 31

23–73%

Ar

H N

NHR1 N

104

CN

626

Functions Containing an Iminocarbonyl Group

As shown in Scheme 32, dimethyl cyanodithioiminocarbonate 105 was converted into 2-methylthio-N,N0 -dicyano-1,3-diaza-2-propenide 106 by reaction with cyanamide in the presence of K2CO3. Alternatively, the reaction of 105 with disodium cyanamide in N,N0 -dimethylacetamide gave disodium N,N0 ,N0 -tricyanoguanidine 107 . NCN MeS

SMe 105

i

ii

67

% 83

%

CN N CN N 106 MeS

–

–

Na+

2Na

+ –

i. H2NCN, THF, K2CO3, ∆, 12 h,

CN N CN N N CN 107

ii. 2Na2NCN, DMAC, 120–140 °C, 2 h,

Scheme 32

N,N0 -diarylcyanoguanidines 109 were synthesized from N-cyano-O-phenylureas 108 and arylamines. In analogy with the reaction in which the Weinreb amide is formed, trimethylaluminum was employed to promote this displacement (Equation (13)) . N

i N H

NH2

R1

CN

ii

N

O

N H

108

R1

CN N H

ð13Þ

109

i. Diphenylcyanocarbonimidate, AcCN, reflux, 2 h ii. Aniline, trimethylaluminum, DCM, 65 °C, 2 h

The highly reactive di(imidazol-1-yl)cyanomethanimide 110 readily reacts at room temperature with both alkyl- and arylamines to yield the corresponding cyanocarboximidazoles 111. In turn, 111 is converted to cyanoguanidines of type 112 in refluxing THF (Scheme 33) .

NCN N

N

N

NCN

R1R2NH N

THF, rt

R1R2N

110

N 111

NCN

R3R4NH N

THF, reflux

R1R2N

NR3R4 112

Scheme 33

6.21.1.1.8

N-Haloiminocarbonyl derivatives

Many of the N-haloguanidines are unstable and/or explosive; therefore, most halogenations of guanidines are carried out on laboratory scale. These compounds are usually prepared by direct elemental halogenation of appropriately substituted guanidines. For example, perfluoroguanidine can be obtained by reaction of guanidine with elemental fluorine. 2-Chloro-1,1-dialkyl guanidines are prepared by oxidation with sodium hypochlorite.

627

Functions Containing an Iminocarbonyl Group

An interesting example, where 2-haloguanidine was prepared by a method other than the direct nitrogen–halogen formation is the reaction of pentafluoroguanidine with alkyl- or arylamines at low temperatures. The initially formed adduct upon warming loses difluoroamine to give a trifluoroguanidine. No further advances have occurred in this area since the publication of chapter 6.21.1.1.8 in .

6.21.1.1.9

N-Chalcogenoiminocarbonyl derivatives

(i) Oxygen derivatives The reaction of hydroxylamines with S-alkyl isothioureas and chlorformamidines 2, cyanamides 7, and carbodiimides 8 all give rise to the formation of the hydroxyguanidines (Scheme 1). N-Alkoxyguanidines are prepared analogously starting from O-alkylhydroxylamines in place of hydroxylamines. They are also synthesized by alkylation of hydroxyguanidines with alkyl halides. However, acylation of hydroxyguanidines gives the corresponding acetoxy- or benzoyloxyguanidines . Recently, guanylations of thioureas with O-benzylhydroxylamine have been described. Construction of benzyloxyguanidine group 113 can be achieved either following the activation of the thiocarbonyl group by mercury(II) oxide and subsequent displacement with O-benzylhydroxylamine or using HgCl2 as coupling reagent . Hydrogenation of the benzyl group using 20% Pd(OH)2 as the catalyst at 0  C yields the hydroxyguanidine derivative 114 (Scheme 34).

S R1HN

i, ii (or iii) NHR2

N R1HN

R1, R2 = alkyl

OBn

iv

NHR2

N R1HN

113

OH NHR2

114

i. BnONH2 .HCl; ii. HgO, Et 3N, Et2O, rt iii. HgCl2, TEA, DMF, rt; iv. Pd(OH)2/C, H2, MeOH, 0 °C, 10 min

Scheme 34

A new convenient reagent for N-hydroxyguanylation has also been described. According to Scheme 35, 1-benzyloxycarbonylthiourea 115 was synthesized from benzyl chloroformate in two steps. Reactions of this protected urea with various amines using HgCl2 in the presence of Et3N furnished hydroxyguanidines 116 in 37–67% yields .

CbzCl

KSCN

CbzNCS

S

H2NOBn CbzHN

NHOBn 115

NR1R2

R1R2HN, HgCl2 Et3N, DMF

CbzHN

NHOBn 116

Scheme 35

(ii) Sulfur derivatives The most convenient route to sulfonyl guanidines consists in the condensation of an arylsulfonyl chloride with guanidine or the reaction of arylsulfonamides with S-alkyl isothioureas. N-(alkylaminosulfonyl)guanidines can be prepared by reacting N,N-dialkyl-N0 -chlorosulfonylchloroformamidines with primary or secondary amines. The reaction of S,S-dimethyl-N-arylsulfonyliminodithiocarbonimidate or N-Ts-carbonimidic dichloride with amines leads to the formation of N-sulfonyl guanidines.

628

Functions Containing an Iminocarbonyl Group

Another method for the synthesis of sulfonyl guanidines involves the reaction of N-sulfonylN0 -alkyl carbodiimides with alkylamines. Cycloaddition reactions of sulfonyl isothiocyanates and guanidines, sulfonyl isothiocyanates and thiourea or N-sulfinyl-sulfonamides and thioureas give rise to the desired sulfonylguanidines . In recent years, a new reagent (117; Equation (14)) capable of guanylating primary amines effectively has been developed . The reaction of pyrazole 117 with aliphatic amines at room temperature affords N-Ts-protected guanidines 118 in quantitative yields, while aniline and t-butylamine are less reactive. No reaction takes place with p-nitroaniline and piperidine. N t-BOCN

N

TsCl, NaH, THF

NH2

N t-BOCHN

N

NHR1

RNH2, THF, rt t-BOCHN

NTs 117

NTs

ð14Þ

118

A series of N-aryl-N0 ,N0 -dimethyl-N0 -trifluoromethylsulfonyl guanidines 120 were prepared by reacting dimethyl cyanamide with triflic anhydride (Tf2O) followed by treatment of intermediary formed 2,3-bis-(trifluoromethylsulfonyl)-1,1-dimethylisourea 119 with aromatic amines (Scheme 36) . Me

Me

Tf2O N C N

Me

OTf

DCM, 20 °C

Me

NHR1

Me

ArNH2

N

N NTf

30–58%

Me

119

NTf 120

R1 = Ph, 2-pyrimidinyl

Scheme 36

HgCl2 or EDCI were applied as coupling reagents to the syntheses of sulfonyl- and sulfamoylguanidines of type 121 from thiourea precursors (Scheme 37, methods A and B, respectively) . Similar results were obtained using HgO . S

i. NaH NH2SO2R1

R1HN

ii. R1NCS

NR2R3 SO2R1 R1HN N

iii (or iv) SO2R1

N Na

70–90%

3

4

121 R1

2

i

= Me, Ph, NH2; R = aryl, alkyl; R = alkyl; phenyl; R = H, Pr

iii. HgCl2, Et3N; (method A) iv. 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI); (method B)

Scheme 37

Synthesis of N,N0 -substituted guanidines 123 was also developed via an aromatic sulfonylactivated thiourea intermediate 122 . A primary amine was first turned into a pentafluoromethyl thiocarbonate. This allowed for the synthesis of the arylsulfonyl-activated thiourea 122 using PbfNHK as nucleophile (Scheme 38). Treatment of 122 with an amine in the presence of Mukaiyama’s reagent produced subsequent guanidine 123 in very good yield. The reaction works for either primary or secondary amine nucleophiles, including the sterically hindered t-butylamine as well as diisopropylamine, both of which are known to cause problems in other guanidine syntheses performed in solution. The above was also adopted to solid-phase synthesis of functionalized amino acids. An amino acid attached to Rink amide MBHA resin was turned into the desired guanidine derivative through direct guanylation with Pbf-activated thiourea .

629

Functions Containing an Iminocarbonyl Group S i, ii

NH2

R1

N H

R1

N H

Pbf

NR1R2 Pbf N N H

iii R1

122

123

i. Pentafluorophenylchloroformate, DIPEA, DCM

O Pbf =

ii. PbfNH2, ButOK, DMSO SO2

iii. R1R2NH, Mukaiyama's reagent, DIPEA, THF, DMF

Scheme 38

N-Sulfonyl guanidines 124 were obtained from the reaction of alkyl isocyanides with aromatic amines in the presence of chloramine T (Equation (15)). The synthesis affords N-tosyl guanidines by an experimentally simple one-pot procedure but, surprisingly, by employing alkylamines, instead of anilines, the reaction did not occur .

N

TEBA, DCM RNC:

+

ArNH2

+

TsNNaCl

R1HN

rt, 20 °C

Ts NHAr

ð15Þ

124

N-Arylsulfonyl-N0 -(pyrimidin-2-yl)-guanidines were prepared by reacting the corresponding N-acylsulfonyl guanidines with pyrimidin-2-yl-trimethylaminium chloride at room temperature for 48 h . As depicted in Scheme 39, 2-mercaptobenzenosulfonylguanidines and corresponding aminoguanidines of type 125 were obtained by selective aminolysis or hydrazinolysis of the 3-alkylamino-1,4,2-benzodithiazine derivatives .

Cl

S

Me

S O

NHR1

i

N

Cl

SH

Me

S O

O

N

NHR2

O NHR1

125 R1 = alkyl, allyl; R2 = alkyl, NH2 i. H2NNH2 or R2NH2, MeOH, 20 °C

Scheme 39

Upon treatment of N-carbamoylmethyl-N0 -tosylguanidines 126 with primary amines, an unprecedented intramolecular transamination reaction was observed . The reaction leading to N-tosylguanidines 128 probably proceeds via 2-imino-4-oxoimidazolidine 127 (Scheme 40). The first synthesis of 4-substituted benzenesulfonyl cyanoguanidines 129 (Equation (16)) was accomplished by treatment of sodium salt of benzenesulfonamide with N0 -substituted-N-cyano-S-methylcarbamidothioates which were obtained by stirring a mixture of N-cyano-S,S0 -dimethylimino carbonate with the desired amine or hydrazine .

630

Functions Containing an Iminocarbonyl Group H2N

NTs

R1NH2

HN

HN

–NH3 H2N

H2 N

Ts N

HN

O

HN

NTs

R1HN

O 126

127

O

128

R1 = Me, Et, Pr

Scheme 40 SO2NH2 N R1HN

CN

N

i

+

17–82%

SCH3

R1HN

CN O2 S N H

R2

R2

ð16Þ

129 R1, R2 = alkyl

i. EtOH, NaOH, DMF, reflux

6.21.1.1.10

N-Aminoiminocarbonyl derivatives

(i) Alkyl and aryl derivatives In general, N-aminoiminocarbonyl derivatives (N-aminoguanidines) can be prepared following the procedures described previously for guanidines, i.e., from the reaction of either hydrazines with amidinium salts, thioureas, cyanamides, carbodiimides and S-alkyl thioureas, or amines with S-alkylisothiosemicarbazide and N-aminocarbonimidic dichlorides. No major improvements have been achieved in this area since the publication of chapter 6.21.1.1.10 in .

(ii) Imino, nitro, nitroso, and azido derivatives A wide range of imino and nitro derivatives of guanidines can be obtained using the well-known Bamberger reaction, which consists in the reaction of aryldiazonium salts with nitroalkyl derivatives. The use of malonic acid instead of nitroalkyl derivative gives 1,5-diaryl-3-arylazoformazanes via a 1,5-diarylformazan intermediate. Although most of the 2-nitrosoguanidines are unstable and decompose to corresponding ureas and nitrogen, the 1,1,3,3-tetraphenyl-2-nitrosoguanidine was obtained by nitrosylation of tetraphenyl guanidine and proved to be a stable solid at 20  C. Alternatively, 3-nitrosoformazans could be obtained by the reduction of 1,5-diaryl-3-nitroformazans with H2S . In recent years, several new methods for the preparation of nitroguanidines have been elaborated. Thus, 3,5-dimethyl-N-nitro-1H-pyrazole-1-carboxamidine (DMNPC; 130) has been prepared by treatment of 1-amino-2-nitroguanidine with pentane-2,4-dione and then applied for introducing N-nitroguanidino functions as precursors of guanidino functions . The reactions of DMNPC with amines were initially carried out in 1,4-dioxane . However, it has been found that better results could be obtained when the reaction is carried out in more polar solvents such as methanol . The usefulness of DMNPC is exemplified by a facile synthesis of agmatine sulfate 131, as shown in Scheme 41. N4-Substituted N1,N8-disubstituted spermidines were obtained analogously. A similar nitroamidination with O-methyl-N-nitroisourea was applied to the synthesis of blastidic acid, a component of amino acid in an antibiotic, blasticidin S .

631

Functions Containing an Iminocarbonyl Group H N

i

NH2.HCl

CbzHN

CbzHN

ii

NNO2

SO42–

NH2 CH3 H3 C

N

H2N

+ NH2

H N

+ H3N

NH2

131 Agmatine sulfate

N NNO2

i. DMNPC, Na2CO3, MeOH, 25 °C, 3 days ii. HCO2H - MeOH, 10% Pd/C, 25 °C, 2 h

130 (DMNPC)

Scheme 41

2-Nitro-1-phenylaminoguanidine 133, 2-nitro-1-ureidoguanidine 134, and 1-(2-nitroguanidino)3-phenylurea 135 were obtained from the reaction of 1-methyl-2-nitro-1-nitrosoguanidine 132 with phenyl hydrazine, semicarbazide, and phenyl carbazide, respectively (Scheme 42). The above compounds were further oxidized with bromine to give the corresponding azo-derivatives 136 .

Me N NO

H2N N

R' NHNH2

NHR' NH

H2N

H2O, 20 °C

N

NO2

132

Br2, H2O

NR' N

H2N

0–5 °C

N

NO2

133 –135

NO2

136

133 R' = Ph 134 R' = CONH2 135 R' = CONHPh

Scheme 42

The synthesis of 15N-labeled nitroguanidine 137 was accomplished by treatment of guanidine sulfate with K15NO3 in concentrated sulfuric acid, as shown in Equation (17). Compound 137 was then reduced to 15N-labeled aminoguanidine 138 with zinc powder in acetic acid . NH H2N

.H SO 2 4

NH2

15

K15NO3

N

H2SO4

H2N

NO2 NH2

15

Zn

N H2N

NH2

ð17Þ

NH2

2

137

138

Moderately stable N-pentafluorosulfanyl(perfluoroalkylamino)azidomethine 140 is obtained from the reaction of NaN3 with imine 139 which, in turn, has been obtained by photolysis of SF5 with N,N-bis-(trifluoromethyl)cyanamide (Scheme 43) .

(CF3)2NCN

+

SF5Cl

hν

Cl

(CF3)2N

N3

+

NaN3

(CF3)2N N SF5

N SF5 139

Scheme 43

140

632 6.21.1.1.11

Functions Containing an Iminocarbonyl Group N
P, N
As, N
Sb, and N
Bi iminocarbonyl derivatives

(i) Phosphorus(III) derivatives Iminophosphoguanidines 141 (ArN¼P
N¼C(NMe2)2) were obtained by the reaction of iminochlorophosphines with silylated guanidine. Examples of this class of compounds include tris(trichlorophosphoranediylamino)carbenium salts 142 (Figure 3) prepared by the photolysis of triazidocarbenium hexachloroantimonate in PCl3 .

N P

N PCl3

NMe2

Cl3P N

N

N PCl3

NMe2 141

Me2N

142

EtO

O

X P

P

Me2N

SbCl6–

EtO

N

R2N

N

R2N

NR2

156

NR2

157

Figure 3

The chemistry of guanidinylphosphines has recently been developed by Munchenberger and co-workers. Thus, dichloro-N-(N0 ,N0 ,N0 ,N0 -tetramethyl)guanidinylphosphine 143 can be obtained by reacting N-trimethylsilyl-N0 ,N0 ,N0 ,N0 -tetramethylguanidine (TMSTMG) with PCl3 (Scheme 44). The analogous difluorophosphine 144 is prepared from either the reaction of fluorochlorophosphine with tetramethyl guanidine (HTMG) or by treatment of triphenylmethylphosphonous difluoride with HTMG. The latter reaction involves unusual cleavage of P
C rather than the P
F bond (Scheme 44) . On the other hand, dichloro-bis-(pyrrolidinomethyleneimino)-phosphine 145 and dichloro-bis-(piperidinomethyleneimino)-phosphine 146 are formed upon treatment of lithiated guanidines with PCl3 (Scheme 44) . From the reaction of HTMG or TMSTMG with dichlorophosphines or chlorophosphines, the corresponding alkyl(aryl)-bis-[N-(N0 ,N0 ,N0 ,N0 -tetramethyl)guanidinyl]phosphines 147 and dialkyl(aryl)-[N-(N0 ,N0 ,N0 ,N0 -tetramethyl)guanidinyl]phosphines 148 were obtained (Scheme 45) . The compounds 147 were subsequently quaternized at the phosphorus atom upon treatment with MeI at 0  C. The substituted guanidinylphosphines 147 and 148 react with Lewis acids, boron trifluoride, and antimony pentachloride to give the phosphonium compounds of type 149 and 150, respectively (Scheme 46) . Triphenylmethylphosphonous dichloride was found to react with HTMG to give chloro triphenylmethylphosphonous N0 ,N0 ,N0 ,N0 -tetramethyl guanidine 151. Triphenylmethylphosphonous N0 ,N0 ,N0 ,N0 -tetramethyl guanidine 152 was further obtained from the reaction of 151 with LiAlH4 followed by treatment with HCl (Scheme 47) . Diphosphine monoxide 154 is formed when the multifunctional 1,2-bis(tritylated)diphosphine monoxide 153 reacts with HTMG, whereas its tautomer 155 can be obtained from the reaction of chlorophosphine 151 with triphenyl methylphosphinic acid fluoride (Ph3C-PH(O)F) as shown in Scheme 48 .

633

Functions Containing an Iminocarbonyl Group i

Cl

72%

Cl

PCl3

P N C(NMe2)2 143

i. TMSTMG, n -hexane, 0 °C to reflux, 2 h

F

F

i P Cl 81%

F

F

ii P N C(NMe2)2

P PPh3 F

F 144

i. 2HTMG, Et2O, –80 °C to rt, 2 h ii. HTMG, CHCl3, 25 °C, 1 h

–

(CH2)n

(CH2)n i

N Li+

PCl3

N

Cl P

N Cl

22%

N

N (CH2)n

(CH2)n

145, n = 0; 146, n = 1 i. Et2O, 0 °C to rt, 2 h

Scheme 44

i R1PCl2

R1P

71 – 75%

N C(NMe2)2

ii

Me

N C(NMe2)2

+

I–

P R1

N C(NMe2)2

N C(NMe2)2

R1 = Me, But, Ph

147

i. 4HTMG, petroleum ether, 0 °C to reflux, 4 h, ii. MeI, Et2O, 0 °C

R1

i

P Cl R2

R1 P N C(NMe2)2

R2

148

A

R1

R2

Yield (%)

Pri

Pri

74

Ph

78

Ph

61

B

Bu

C

Ph

t

i. TMSTMG, petroleum ether, 0 °C to reflux, 3 h

Scheme 45

(ii) Phosphorus(V) derivatives Two major classes of phosphorus(V) derivatives described in comprised (i) guanidinylphosphoric diamides 156 obtained from the reaction of phosphoryl chlorides with guanidines, and (ii) bis-(dialkylamino)methylenephosphoramidic esters 157 generated by the reaction of dichloromethylenephosphoramidic compounds with dialkylamines (Figure 3).

634

Functions Containing an Iminocarbonyl Group

Ph

2BF3.Et2O

Ph

Et2O, –50 °C, 2 h

Ph

–

+ P N C(NMe2)2 Ph

F3B

Ph P P Ph

N C(NMe2)2 F3B

N C(NMe2)2

149

+

R1

i P N C(NMe2)2

R1

Ph

–

Ph P Cl

SbCl6

N C(NMe2)2 R1 = Ph; 55% R2 = TMG; 60%

150 i. 2SbCl5, Et2O, –80 °C, –SbCl3

Scheme 46

Cl Tr

P Cl

Cl

i

Tr

84%

H

ii, iii, iv

P

Tr

N C(NMe2)2

Tr = Ph3C–

.2HCl

P N C(NMe2)2

152

151 i. TMSTMG, toluene, rt, 3 h; ii. LiAlH4, Et2O, 0 °C to rt, 1 h iii. H2O, rt; iv. toluene, 1 M HCl/Et2O, rt, 71%

Scheme 47

O PhC P H F

O P P FP Tr Tr

i

Cl

Ph3C–PCl2 Et3N, DCM, rt, 2 h

+

HTMG

(Me2N)2C N

O P P F Tr Tr

153

Cl Tr

154

+

P

Tr

N C(NMe2)2

H P O F

ii

151

Tr (Me2N)2C N

P F P O

Tr 155

i. CDCl3, rt, 1 h; ii. Et 3N, DCM, rt, 5 h

Scheme 48

Functions Containing an Iminocarbonyl Group

635

Recently, phosphorus pentachloride has been found to react with 2 equiv. of TMSTMG to give bis-N-(N0 ,N0 ,N0 ,N0 -tetramethyl)guanidinyltrichlorophosphorane 158 (Equation (18)) . i

+

PCl5

2TMSTMG

Cl –2MeSiCl 67%

Cl N C(NMe2)2 P N C(NMe2)2 Cl

ð18Þ 158

i. Et2O, 0 °C, 2 h

The phosphorus compounds 147 react readily with sulfur, selenium, and tellurium to give the corresponding chalogenide derivatives 159 (Scheme 49) .

R1P

X, i or ii

N C(NMe2)2 N C(NMe2)2

N C(NMe2)2 R1 P N C(NMe2)2 X

147

159 R1

X

Me

S

78

i

But

S

86

i

Ph

S

91

i

Ph

Se

79

ii

Ph

Te

71

ii

Yield (%) Conditions

i. 1/8 S, toluene, rt, 2 h; ii. Se or Te, rt, 3 days

Scheme 49

As shown in Equation (19), treatment of the chlorophosphonous guanidine 151 with Et3N in H2O gives triphenyl methylphosphonous N0 ,N0 ,N0 ,N0 -tetramethyl guanidine 160 . Cl Tr

P

Et3N, H2O Tr

N C(NMe2)2 151

O P H N C(NMe2)2

ð19Þ

160

A series of guanidine-containing phosphorylamides 161–166 have been prepared in the reaction of the appropriate chlorophosphoryl compounds with either HTMG or TMSTMG (Scheme 50). In contradistinction to guanidinylphosphine 147, the phosphoryl amide 161 undergoes N-alkylation with methyl iodode to give the ammonium salt 167 . fluorides 168 The organophosphorus N-(N0 ,N0 ,N0 ,N0 -tetramethyl)guanidine (R
P(F)N¼C(NMe2)2; R = t-Bu, Ph) were synthesized and oxidized by sulfur, selenium, and tellurium as well as by the urea-H2O2 1:1 adduct to give the phosphonic acid derivatives 169–172. Compound 168 (R = Ph) undergoes a Staudinger reaction with triphenylmethyl azide to produce the phosphine imide 173 (Scheme 51) . A convenient synthesis of thiophosphinyl guanidines 174 has also been described . The reaction sequence involves initial preparation of sodium thiophosphinyl cyanamide Na[Ph2P(S)NCN] which then reacts with alkyl- and arylammonium chlorides [RNH3]Cl to give the corresponding alkyl- and arylammonium thiophosphinyl cyanamides. The latter compounds, when heated at 130–190  C, rearrange to N-alkyl(aryl)-N0 -thiophosphinyl guanidines 174 in a Wo¨hler-type reaction (Scheme 52).

636

Functions Containing an Iminocarbonyl Group O

163

R1

P

O

N C(NMe2)2 R2

R1

R1 = Me; R2 = Et2N R1

= Ph;

R2

R1

O P

= Ph

Cl

O P

R2

Cl

Cl

Cl 2 equiv.

Cl

R1

O

Cl P

N C(NMe2)2

P Cl

O

Cl

Cl

HTMG

Cl

162

Cl

P

2 equiv.

O

N C(NMe2)2

R1 = Ph, Tr

R1

O

P

1

P

161

N C(NMe2)2

R

4 equiv.

N C(NMe2)2

R1 = Me, But, Ph

164 O O

Cl P

Cl

i. TMS

P

Cl

O

ii.

Cl

O O

N C(NMe2)2

O

P

P

P Cl

N C(NMe2)2

(Me2N)2C N 165

MeI

P But

(Me2N)2C N

R1 = Me

Cl Cl

O

N C(NMe2)2

P Me

But

N C(NMe2)2 N C(NMe2)2 Me

166

167

Scheme 50

NTr 1

R

P

F

173

N C(NMe2)2

i. Toluene, rt, 2 h

TrN3, i %

87

F R1

P N C(NMe2)2 168

O

H2O2 /urea, i

R1

63–75%

P

i. 0 °C to rt, 2 h

X, i

X 1

R

P

F N C(NMe2)2

169 , X = S; i. toluene, rt, 2–16 h, 73–87% 170 , X = Se; i. toluene, rt to 60 °C, 61–67% 171 , X = Te; i. toluene, rt, 3–16 h, 44–52%

Scheme 51

F 172 N C(NMe2)2

I

–

637

Functions Containing an Iminocarbonyl Group S Ph2P

–

+

Na2NCN

Na

R1NH3+ Cl-–

S

+

R1NH3

Ph2P

Cl

NCN

130–190 °C

S

+

–

Ph2P NCN

S Ph2P

NH2 N C NHR1 174

R1 = Bun, But, c -hexane, Ph, p-ClC6H4

Scheme 52

Phosphoryl thiourea 175 can be converted into N1,N1-diphenyl-N3-dialkoxyphosphoryl guanidine 177 in three steps (Scheme 53). First, the compound 175 is reacted with allyl bromide to give S-alkenylated product, which upon vacuum distillation in the presence of catalytic amount of hydroquinone undergoes
-elimination of allyl mercaptan giving rise to the formation of N-phenyl-N1-dialkoxyphosphoryl carbodiimide 176 in 50% yield. The final product 177 is obtained by reacting 176 with aniline at room temperature .

O (PriO)2P

Br, Et3N

S N H

O (PriO)2P

NHPh

∆, 0.05 mmHg

S N

NHPh

-

SH

175 NH2

O (PriO)2P

N

C

NPh

O (PriO)2P

rt

176

NHPh N

NHPh

177

Scheme 53

(iii) As, Sb, and Bi derivatives The only report mentioned in referred to dative-bonded complexes of guanidines and bismuth or antimony trihalides. In 1994 a reaction of TMSTMG with MeAsCl2 leading to methyl [N-(N0 ,N0 ,N0 ,N0 -tetramethyl)guanidinyl]chloroarsine 178 was described (Equation (20)) . TMSTMG, rt, 2 h MeAsCl2 –Me3SiCl

Me As N C(NMe2)2 Cl

ð20Þ

178

An interesting complex between antimony(III) and guanidine is also described . 1,2,3-Triisopropyl guanidine reacts with antimony tris(dimethylamide) (Sb(NMe2)3) to give complex 179 in which the Sb is chelated by a [C(N
Pri)3]2
dianion and a [iPrN)2CNHPri]
monoanion (Equation (21)).

638

Functions Containing an Iminocarbonyl Group

PriHN

Sb(NMe2)3

C NPri PriHN

Pri Pri 2– N 3 + N– PriN Sb NHPri N N Pri Pri

ð21Þ

179

6.21.1.1.12

N
Si, N
Ge, and N
B iminocarbonyl derivatives

According to chapter 6.21.1.1.12 in , N-silylated guanidines 180 (Figure 4) and guanidinium salts [Me2N)2CHTMS]+ Hal
were prepared by reacting the corresponding guanidine with a chlorosilane in the presence of a base and in the absence of added base, respectively. H+ N Ar3B–

NMe2 N TMS

NMe2

180

NHR NHR

181

Figure 4

N-Borated guanidines were represented by triarylboron complexes 181 (Figure 4) and no N-germylated guanidine derivatives were described in . Recently, N-silyl-N0 ,N0 ,N0 ,N0 -tetramethyl guanidine (TMSTMG) was applied to the synthesis of 2-azonioallene salts of type 182 (Equation (22)) . Cl

SbCl6–

Me2N + NMe2

i

NSiMe3

+ Me2N

NMe2

NMe2

Me2N N

–Me3SiCl 78%

Me2N

NMe2

SbCl6–

ð22Þ

182 i. 1,2-dichloroethene, –50 °C to –20 °C

23 °C, 5 h

A new class of Si
N bonded compounds 183 was obtained from the reaction of biguanide and its N-alkyl derivatives with diorganosilanes R1R2SiNH2 (R1,R2 = Ph; R1 = Me, R2 = Ph) . The reaction proceeds via SiH/NH dehydrocoupling and affords corresponding oligomeric 1,4-bis-(silyl)biguanides (Equation (23)).

H2N

N NH

NHR3 NH2

R1R2SiNH2 THF, reflux, 16 h

H

R1 H Si N R2

N

R3 N

NH NH H Si R1 R2

R3 = H, Pr, cyclohexyl

H

ð23Þ n

183

Guanidinate anions of type 184 are generated by the reaction of lithium bis(trimethylsilyl)amide (LiN(SiMe3)2) with 1,3-alkyl carbodiimides (R1,R2 = iPr, cyclohexyl) (Scheme 54). Lithium salts 184 were isolated in pure form and used for preparation of a series of bis- and monoguanidinate complexes of Zr and Hf , Nb and Ta , as well as Yb and Sm . As depicted in Equation (24), the [2+2] cycloadditions that take place between imidozircocene complexes and 1,3-di-(trimethylsilyl)carbodiimide give other types of diazametallacycle complexes 185 .

639

Functions Containing an Iminocarbonyl Group

(Me3Si)2N– Li+

+

Me3Si

R1N=C=NR2

R1

Et2O, rt, 4 h

N

N

SiMe3 N

R

Me3Si

M(X)n

2

R1

N

N

Li

SiMe3 N

R2

M(X)n

184

Scheme 54

Cp2Zr

But N

NBut

Me3SiN C NSiMe3

Zr

C NSiMe3 N SiMe3

ð24Þ

185

6.21.1.2

Iminocarbonyl Derivatives with One Nitrogen and One P, As, Sb, or Bi Function

6.21.1.2.1

N-Alkylimino derivatives with one P or As function

Title compounds 186 (Figure 5) were usually obtained by Michaelis–Arbuzov reaction of the carbamimidic chlorides with trimethyl phosphite (P(OMe)3). Another method for preparation of 187 consists in the attack of alkali metal organoarsenides at N,N0 -dialkyl carbodiimides followed by hydrolysis or alkylation of the intermediary formed (lithioamidino)arsines .

Bun NR'R3

CO2Et RN

O P MeO OMe

R'N

NR2R3 ArN P(OR1)2

AsR22

186

O

187

189

CF3 N Ph P(OEt)2

PhN

PhN PR1R2

O 190

O

N(Ph)R3

191

RO

NEt N

P(OR)2 O

195

Figure 5

Recently, the phospha(III)guanidine compounds of the general formula Ph2PC(NR) (NHR);R = Pri, cyclohexyl) have been prepared in good yields as described in Scheme 55. Lithium diphenylphosphide obtained by treatment of Ph2PH with BuLi is allowed to react with suitable carbodiimide giving the corresponding lithium phospha(III)guanidinate. Quenching the reaction with triethylamine hydrochloride yields the neutral phospha(III)guanidines 188 .

640

Functions Containing an Iminocarbonyl Group Ph P Ph

R1 N i, ii

R1

Ph2PH Ph

N

P Ph

Li Li

N

NR1

iii 71%

R1

N R1

Ph2P

R1 = Pri, cyclohexyl

NHR1 188

i. BuLi in hexanes, THF, 0 °C, 0.5 h ii. Carbodiimide, THF, 0 °C to rt, overnight iii. Dry [HNEt3][Cl], THF, rt, 1 h

Scheme 55

6.21.1.2.2

N-Arylimino derivatives with one P function

There are three methods described in for the preparation of amidinophosphonates of type 189 (Figure 5). The first involves the reversible reaction of N,N0 -diphenyl carbodiimide with a phosphite triester. The second method consists in the direct aminolysis of iminochlorides of general formula ArN = C(Cl)P(O) (OR1)2. The third method is based on a Michaelis–Arbuzov reaction of the amidinochlorides with trialkyl phosphites. When a chloroalkylcarbodiimide was used instead of carbodiimide in a variant of a Michaelis–Arbuzov reaction, the corresponding alkylideneamidophosphonate 190 could be obtained. Amidinophosphines 191 (Figure 5) are usually prepared by the addition of phosphines containing PH or PSi bond across the C¼N bond of carbodiimide. Thus, the reaction of monophenylphosphine (PhPH2) with carbodiimide gives the bis(amidino)phosphine and analogous reaction of carbodiimide with diphenylphosphine (Ph2PH) leads to the formation of mono(amidino)phosphine . In 1995 Komalov and co-workers described a facile synthesis of novel dialkyl-Narylimino(amidino)phosphonates 192 . The addition of anilidophosphines to carbodiimides carried out at room temperature afforded the compounds 192 in 87–97% yield (Equation (25)). NR2 NHR3 R1O P 3 OR1 NR

R1O P NHR2

R3N=C=NR3

+

R1O

ð25Þ

192 1

i

2

3

R = Et, Pr ; R = Ph, Tol; R = Ph, cyclohexyl

The C-phosphorylated N,N-dimethyl-N0 -tolyl formamidines 194 are obtained starting from N,N-dimethyl-N0 -tolyl formamidines, which reacts with PBr3 to give the dibromophosphine 193. The above reaction represents the first example of electrophilic substitution at a formamidine carbon atom. Then, the intermediate 193 upon treatment with dialkylamine and elemental sulfur is converted into the desired C-phosphorylated amidines 194 in 40–44% yields (Scheme 56) .

6.21.1.2.3

N-Acylimino derivatives with one P function

N-Acylimino derivatives are usually generated from dichloromethyl isocyanate precursors bearing the dichlorophosphine moiety. First, in the reaction with alcohols they are converted to chloroimines, which, on treatment with diethylamine, give the N-acyliminoamidinophosphonates 195 (Figure 5). No major progress has been made since the publication of .

641

Functions Containing an Iminocarbonyl Group

Me

Me N Me

N

+

Br2P

Pyr PBr3

Me

Et3N, 0 °C

N

Me N Me

193 S (R1R2N)2P

i. R1R2NH 1

ii. /8 S, rt, 8 h

Me

N

Me N Me

R1, R2 = Me, Et

194

Scheme 56

6.21.1.2.4

N-Haloiminocarbonyl derivatives with one P function

Phosphorylnitrile oxide generated in situ from the corresponding hydroxamic acid chloride is easily converted into phosphorylamidoxime 196 upon treatment with aliphatic and aromatic amines, benzhydrazide, or semicarbazide (Scheme 57). The reactions are carried out at room temperature or at reflux for 5 min in solvents such as chloroform and acetonitrile. In the case of semicarbazide the hydroxamic acid chloride is treated with KOH in PriOH . O (PriO)2P

NOH

O (PriO)2P

R1NH2 C

Cl

N O

O (PriO)2P

NOH NHR1

196 R1 = Bu, Ph, 4-NH2C6H4, 4-O2NC6H4, NHC(O)NH2, NHC(O)Ph

Scheme 57

6.21.1.2.5

Hydrazono derivatives with one P function

N0 -Aryl-C-(dialkoxyphosphoryl)formamidrazones (197; X = NMe2) (Figure 6) were obtained from the reaction of corresponding chlorohydrazono derivatives with aqueous solution of amines or phenylhydrazine. Similarly were obtained the azido and nitrohydrazones (197; X = N3, NO2). The 1,3-addition of mono- or dialkylamines to nitrile imines (Ar2P
N

N+C
P(S) (NR1R2)2) furnished N0 -phosphineformamidrazones 198 (Figure 6). (Arylhydrazono)arylazomethyl)phosphonates 199 (Figure 6) were obtained by coupling reaction of phosphinyl acetaldehyde with diazonium salts. Alternatively, the coupling reaction of the triphenylphosphine acetic acid with 2 molar equiv. of diazonium salt furnished the bis(arylazo)methylenephosphine 200 (Figure 6). Oxidation of the dialkoxyphosphorylamidrazone with silver(I) oxide gave the N-(arylazo)dialkoxyphosphoryl)methyleneamine 201 (Figure 6). No further advances have occurred in this area since the publication of chapter 6.21.1.2.4 in .

6.21.1.2.6

Diazonium derivatives with one P function

Title diazomethane derivatives 202 (Figure 7) are usually obtained by the treatment of diazomethylphosphonates with dinitrogen pentoxide (N2O5). Since the publication of chapter 6.21.1.2.5 in no further advances have occurred in this area.

642

Functions Containing an Iminocarbonyl Group X ArHN

NPr2i

R1 P R2

N

Ar

O

Ar

197

N=NAr

ArHN NPr2i

H N N P

P

N

NPr2i

P(OR)2 O

S 198

199

X = NMe2, N3, NO2

N=NAr

N=NAr

ArHN

RN

– BF4

N

P(OR1)2

PPh3 + 200

O 201

Figure 6

NO2 R1 P R2

N2 O

202

NR22

+ R22N –

X

NR22

+ R22N

NR22

OEt

NR22

+ R22N

Ph

P

P NR22

P OEt

O

203

204

O

Ph

205

Figure 7

6.21.1.2.7

N,N-Dialkyliminium derivatives with one P function

In chapter 6.21.1.2.6 in the following methods were described for preparing the title compounds. For the syntheses of phosphaallylic salts and phosphorylated amidinium salts, N,N,N0 ,N0 -tetramethylimidoyl chloride is used as starting material: (i) it reacts with 0.5 molar equiv. of tris(TMS)phosphane (P(TMS)3) to give compounds 203 (Figure 7); (ii) upon treatment with triethyl phosphite the monophosphorylated amidinium salts 204 are obtained; and (iii) it undergoes a standard Michaelis–Arbuzov reaction with alkyl diphenylphosphinite having only one displaceable alkyl group to give the salt 205. Although the majority of phosphaalkenes show a polarity P+C
of P¼C double bond, in a number of P-acyl, P-dithiocarboxyl, and P-thiocarbamoyl-phosphaalkenes, an inverse polarity P
C+ of the multiple bond is observed. Recently, the synthesis, structure, bonding, and coordination chemistry of these derivatives have been investigated in detail . Replacement of the P-silyl group in P-trimethylsilyl-substituted phosphoalkanes 206 by acyl, dithiocarboxy, and thiocarbamoyl functions leads to the compounds 207, 210, and 211, respectively (Scheme 58). Based on a significant deshielding of the 31P NMR resonances and X-ray structure analysis, the electronic configuration was described by canonical formulas 207, 208, and 209 (Scheme 58). X-ray structure analysis of 210 confirmed the existence of multiple bonding of planar carbenium center (C5) to the planarly configured atoms C(2)
N(1) and C(2)
N(3). Reactivity of the carbonyl-functionalized phosphaalkanes 207 toward protic acids, Lewis acids, and alkylating and silylating agents were investigated by Weber and co-workers . It was found that the reaction with protic acids and alkylating agents occurred at two-coordinate phosphorus atom yielding the phosphanyl-substituted amidinium cations 212 and 213. Silylation with Me3SiOSO2CF3 resulted in the attack at the oxygen atom (formation of 214). Also Lewis acid B(C6F5)3 was ligated at the oxygen atom of carbonyl group to give the adduct 215 (Scheme 59). The structures of the adducts of 207 with the homologous Lewis acids AlMe3, GaMe3, and InMe3 were also investigated in detail. AlMe3 was ligated to the oxygen atom of the carbonyl

643

Functions Containing an Iminocarbonyl Group O R1

NMe2

O

P

P R1

NMe2

207

–

–

O

NMe2 + NMe2

P R1

208 R1

NMe2 + NMe2

209

COCl S

CS2

NMe2

Me3SiS

NMe2

Me3SiP

P NMe2

206

NMe2

210

PhNCS

Me3Si

S N

Ph

NMe2 P NMe2

211

Scheme 58 O R1

Me NMe2 + P NMe2

–

SO3CF3

213

CH3OSO2CF3 R1 O

NMe2 + NMe2

P H BF

HBF4/Et2O

O

NMe2 P

R1

NMe2

Me3SiSO2CF3

SiMe3 O NMe2 – + P SO3CF3 NMe2 R1

–

212

207

(C6F5)3B O

214

NMe2 + NMe2

P R1 215

Scheme 59

group; 2 molar equiv. of GaMe3 were added to the oxygen and phosphorus atom, and InMe3 was bound to the phosphorus center of the phosphaalkane (Scheme 60) . Molecules of type 210 and 211 were found to behave as multidentate ligands in transition metal chemistry (Equation (26)). Thus, they reacted with (CO)5MBr (M = Mn, Re) to afford tricyclic complexes 216 and 217 . Complexation of 207 with transition metal carbonyls took place at the pnictogen atom resulting in the complexes of type 218 (RC(O)P[M(CO)n]C(NMe2)2) (R = t-Bu, Ph; M = Ni, n = 3; Fe, n = 4; Cr, n = 5) (Equation (27)).

644

Functions Containing an Iminocarbonyl Group –

AlMe3 O NMe2 + P NMe2 R1 AlMe3

–

O

NMe2 P

R1

InMe3

O

InMe3

P R1

NMe2

NMe2 + NMe2

207

2GaMe3 –

Me3Ga O

GaMe3 P

R1

NMe2 + NMe2

Scheme 60 S X

(CO)5MBr

210, 211

–Me3SiBr, – 4CO

NMe2

L

L M

P P L L L M Me2N S Me2N L

NMe2

ð26Þ

X

L = CO, M = Mn, Re; 216 , X = S; 217 , X = NPh

O

NMe2

O P

P R1

R1 M(CO)4

NMe2 207

6.21.1.3 6.21.1.3.1

NMe2 + NMe2

ð27Þ

218

Iminocarbonyl Derivatives with One Nitrogen and One Metalloid Function Silicon derivatives

A compound of this class, silanecarboximidamide 219 (Figure 8), was prepared by the reaction of N,N0 -diphenyl carbodiimide and bis(TMS)mercury . Since the publication of chapter 6.21.1.3.1 in no further advances have occurred in this area.

N(Ph)TMS R1N

PhN TMS

R2 N

NMe2 2

BR

–

PhN

2

B 4

R 219

220

R1

+ N R3 R4

221

Figure 8

PhN

N

+ – N Bu B H Bu 222

645

Functions Containing an Iminocarbonyl Group 6.21.1.3.2

Boron derivatives

N-Alkylboranecarboximidamide 220 (Figure 8) is formed as a by-product of the reaction of -lithio-N,N-dimethylacetamide with bromodimethylborane. Other examples of borane carboximidamides 221 and 222 can be prepared by reacting phenyl isocyanide with boraneamide and 2-(dialkylboryl)aminopyridine, respectively . Recently, novel types of [amine-bis-(amidinium) hydroboron2+] 225 and [amine-bis(triethylamidinium)hydroboron2+] 226 cations have been obtained . First, the cyano groups of 223 are activated by ethylation employing Et3OBF4 to give [amine-bis(ethylnitrilium)hydroboron2+] tetrafluoroborates 224. Then, nucleophilic addition of ammonia and diethylamine gives 225 and 226, respectively (Scheme 61).

CN

C N Et

Et3OBF4

A HB CN

DCM, reflux, 25 h

i –

A HB

2+

H2N

2+ 2BF4

C NHEt

C N Et

–

2BF4

A HB C NHEt H2N

223

224 225 ii

2+

Et2N C NHEt

–

2PF6

A HB C NHEt Et2N

i. Liquid NH3, –30 °C, 5 min ii. Et2NH, rt, 5–10 min, then H2O, NaPF6

226

Scheme 61

6.21.1.4 6.21.1.4.1

Iminocarbonyl Derivatives with One Nitrogen and One Metal Function Main metal derivatives

The trialkylstannyl and trialkylplumbyl formamidines 227 (Figure 9) were obtained by the 1,1-addition of a metal amide to an aryl isocyanide . Adducts of InMe3 with aryl isocyanides of general structure Me3InCNR (228, R = 4-MeC6H4, 4-OMeC6H4) react slowly at room temperature with pyrrolidine to give the insertion products 229 (Scheme 62). The same compounds were obtained by reacting InMe2Pyrr 230 with corresponding isocyanides .

6.21.1.4.2

Transition metal derivatives

The nucleophilic attack of azetidine at the carbon atom of coordinated isocyanide ligands of the neutral or cationic complexes of Pd and Pt resulted in the formation of the diaminocarbene complexes 231 and 232, respectively (Figure 9). The reaction of tetrakis(t-butyl isocyanide)rhodium(I) tetrafluoroborate with dimethylamine and diethylamine gave 1:1 adducts 233 containing a -bonded amidinium cation .

646

Functions Containing an Iminocarbonyl Group NR22

NHR

ArN

N

MR13

M(PPh3)Cl2

227

231

M = Sn, Ar = 4-MeC6H4, R1 = R2 = Me M = Pb, Ar = Ph, R1 = Bu, R2 = Et

+ OMe

HN N

R2N

–

BF4

Rh(C But

M(PPh3)Cl

–

NBut)3 BF4

HN + 233

232 M = Pd, Pt

Figure 9

NR InMe3

RNC, i

+

Me3In

ii

iii Me2In N

N

Me3InCNR

228

229

230

i. n-Hexane, rt, 24 h ii. Pyrrolidine, n-hexane, rt, 33 days iii. RNC, n-hexane, rt, 2 months

Scheme 62

Pentacarbonyl {(dimethylamino)[methoxy(phenyl)methyleneamino]carbene} complexes of molybdenium(0) and tungsten(0) 234 react with chloroauric acid to give chloro {(dimethylamino)[methoxy(phenyl)methyleneamino]carbene}gold(I) 235 and trichloro {(dimethylamino)[methoxy(phenyl)methyleneamino]carbene}gold(I) 236 (Scheme 63) . Compounds 235 and 236 react with boron tribromide to give the tribromo derivative 237, which, in turn, is converted into triiodo gold complex 238 upon treatment with boron triiodide .

(CO)5M

NMe2 Ph N OMe 234

HAuCl4

ClAu

NMe2 Ph N OMe

Cl3Au

235

M = Mo(II), W(III)

Br3Au

NMe2 + Ph N OMe

BI3

237

236

I3Au

NMe2 Ph N OMe 238

Scheme 63

NMe2 Ph N OMe

PBr3

647

Functions Containing an Iminocarbonyl Group

Isocyanide complex [AuCl(CNBut)] 239 reacts with terminal alkynes in diethylamine to give the corresponding alkynyl(carbene) complexes 240 and 241 (Scheme 64) . NHBut RC C Au

i [AuCl(C

240 NEt2

R = H, But, SiMe3

NBut]

239

ii

ButHN

NHBut Au C C(CH2)5C C Au

Et2N

NEt2 241

i. RC CH, Et2NH, rt, 17–24 h ii. HC C(CH2)C CH, Et2NH, rt,14 h

Scheme 64

As shown in Equation (28), the insertion reaction of aryl isocyanides with zirconium amido silyl complex leading to the compound 242 has recently been described . Si(SiMe3)3 Zr NMe2 Me2N NMe2

ArNC

Me2N Me2N

Si(SiMe3)3 Zr NMe2

Ar

NMe2

N

Me2N

Zr Si(SiMe ) 3 3 NMe2

C N Ar

ð28Þ

242 Ar = 2,6-Me2C6H3

The carbodiimide complex 244 and the four-membered metallacycles 245 are obtained from the reaction of the isocyanide metal precursors (243, M = Co, Rh) with aryl azides (Scheme 65). As evidenced by NMR spectroscopy, the compound 245 exists in equilibrium with isomer 246 .

6.21.2

IMINOCARBONYL DERIVATIVES CONTAINING AT LEAST ONE P, As, Sb, OR Bi FUNCTION (AND NO HALOGEN, CHALCOGEN, OR NITROGEN FUNCTIONS)

6.21.2.1

6.21.2.1.1

Iminocarbonyl Derivatives with One P, As, Sb, or Bi Function and One P, As, Sb, or Bi Function Bis(phosphino)iminocarbonyl derivatives

Phosphorus compounds of type 247 (Figure 10) in which the carbon atom of the iminocarbonyl group is attached to two three-valent phosphorus atoms were found to be unstable, and, therefore, little is known about their properties. The more stable (diazomethylene)-bis(phosphonous diamides) 248 were obtained by addition of the lithium salt of the bis(phosphanyl)diazomethane to the chlorophosphane . [Bis(diisopropylamino)phosphonio][chloro(isopropylamino)phosphino]diazomethane 249 is readily available by addition of the lithium salt of [bis(diisopropylamino)phosphino]diazomethane to dichloro(isopropylamino)phosphane (Equation (29)) . Interestingly,

648

Functions Containing an Iminocarbonyl Group

Me3P

M

ArN3 CNR

M

Me3P

–N2

+

NAr

Me3P

C

NR

N Ar

RN

RN 243

M

244

245

M = Co, Rh; Ar = Ph, Tol; R1 = C6H11, bn

Me3P

Co

NC6H11

C N Ph

H11C6N

Co

Me3P PhN

C

NC6H11

N C6H11 246

245

Me3P

Co

+

CNC6H11

H11C6N + NPh

Scheme 65 Ph P(NR2)2

P TMS N2

ArN

P(NR2)2

P Ph TMS 247

248

Figure 10

(phosphino-(P-chlorophosphonio)diazo derivative 252, obtained by addition of bis(diisopropylamino)phosphonium salt 250 to P-chlorodiazomethylenephosphorane 251 at –30  C, appeared to be unstable with respect to dinitrogen elimination, which began at
23  C and led to the corresponding carbene 253 (Scheme 66) . R

N2 P C

+

i

R

RPCl2

Li

R

N2

R

P C P Cl

R

ð29Þ 249 R = Pr2i N i. THF, –78 to 0 °C, 1 h

Cl R P C N2 R

–33 °C

+

250

+

–

R2P TfO

R

251

R P

Cl R P R C N2 252

R = Pr2iN

Scheme 66

>–23 °C R

R P

Cl + R P C R

–N2 253

649

Functions Containing an Iminocarbonyl Group

Diphosphirenium salt 254 reacts with t-butyl isocyanide at
50  C to give four-membered heterocycle 255 featuring a 32-phosphorus–carbon double bond . The latter compound upon treatment with nucleophiles such as butyl- or methyllithium forms a phosphorus heterocycle 256 (Scheme 67).

NR2 +

P

+

NR2 But–NC

NR2 P NR2

–50 °C

– BF4

C N But

P

NR2 P NR2

NR2 –

BF4

254

NR2

NR2 P P+ NR2 C – BF4 N But

R1–Li

NR2

R1P

P C N

255

NR2 But

256

R = Pri; R1 = Me, Bu

Scheme 67

Alkyl and aryl isocyanides are able to cleave the P¼P bond in the metallodiphosphenes of type 257 to give either the 3-diphosphiranimine 258 or 2,4-diimino-1,3-diphosphetanes 259 (Scheme 68) .

R1

P P

R2

N RNC

RNC R1 P P R2

N

R 257

258

R P R2

R1 P N

R 259

R = Ph, 2-MeC6H4

R = C6H11, bn

R1 = cp*(CO)2Fe, C(SiMe3)3

R1 = cp*(CO)2Fe

R2 = C(SiMe3)3

R2 = 2,4,6-Bu3tC6H2

Scheme 68

6.21.2.1.2

Bis(phosphinyl)iminocarbonyl derivatives

This class of compounds containing five-valent phosphorus atoms includes diphenyl-, dialkoxy-, diamino-, alkoxyamino-, and alkoxyfluoro-phosphinyl derivatives, all of which can be synthesized according to the following methods . (a) From carbonimidic dichlorides and organophosphorus reagents, such as (RO)2P(O)R and Ph2P(O)(OR), were obtained (arylcarbonimidoyl)bisphosphonic acid esters 260, bis(diphenylphosphinyl)methylene)arylamines 261, respectively (Figure 11). Analogously, the Michaelis–Arbuzov reaction of phenylsulfonylcarbonimidic dichloride with (RO)3P gives derivatives 262. (b) From carbimidic dichlorides by metal–halogen exchange with Me2TlP(O)Ph2 the compounds 261 are produced (Figure 11). (c) (Diazomethylene)bisphosphonates 263 are prepared by treatment of the corresponding C
H active methylene precursor with tosyl azide in the presence of potassium t-butoxide. (d) Reaction of the lithium salt of the thioxophosphoranyldiazomethane with chlorophosphane derivatives leads to the phosphinothioyl compounds 264 (Figure 11). (e) P,P0 -(carbonimidoyl)bis(phosphonic amide) 265 is obtained from the reaction of phosphorus(III) acid anhydride with an aryl isocyanate (Figure 11).

650

Functions Containing an Iminocarbonyl Group P(O)(OEt)2

P(O)Ph2

ArN

ArN

P(O)(OR)2 PhSO2N

P(O)(OEt)2

P(O)Ph2

P(O)(OR)2

260

261

262

P(S)R22

P(X)R2 N2

N2 P(X)R2

P(O)(NEt2)2 PhN

P(S)R12

263

264

X = O, S R = OMe, OEt, Ph

R1 = Ph, NMe2, NPr2i

P(O)(NEt2)2

265

R2 = But, NPr2i

Figure 11

6.21.2.1.3

Iminocarbonyl derivatives with P function and one P, As, Sb, or Bi function

Since the publication of chapter 6.21.2.1.1 no major advances have occurred in this area.

6.21.2.1.4

Iminocarbonyl derivatives with one As, Sb, or Bi function and another As, Sb, or Bi function

The bis(3-valent) organometallic diazomethanes depicted in Figure 12 as 266 were prepared by treating the arsino-, stibino-, or bismuthino-dimethylamides with diazomethane. From two-step reactions of this type, mixed organometallic derivatives were also obtained. MMe2 N2 MMe2 266

M = As, Sb, Bi

Figure 12

No advances have occurred in this area since the publication of chapter 6.21.2.1.2 .

6.21.2.2

6.21.2.2.1

Iminocarbonyl Derivatives with One P, As, Sb, or Bi Function and One Si, Ge, or B Function Iminocarbonyl derivatives with one P function and one Si, Ge, or B function

(i) Silicon derivatives The well-known compounds in this class are phosphorus-containing silyldiazomethane derivatives 267 (Figure 13). Dialkylphosphanylsilyldiazomethanes (X = lone pair, R1,R2,R3Si = TMS, R4 = R5 = But), dialkylaminophosphanylsilyldiazomethanes (X = lone pair, R1,R2,R3Si = TMS, R4, R5 = dialkylamino) were prepared by reacting the lithium salt of the (trimethylsilyl)diazomethane with the desired chlorophosphanes. However, silylated -diazo phosphonates (X = O, R1,R2,R3Si = TMS, TBDMS, SiPri3, R4,R5 = OMe, OEt) and phosphonothioic

651

Functions Containing an Iminocarbonyl Group

diamides (X = S, R1,R2,R3 = TMS, SiPh3, R4,R5 = NPri2) could be obtained by reacting lithiated diazo phosphonates with corresponding silyl electrophiles (chlorides or triflates). -Diazo phosphine sulfides (X = S, R1,R2,R3Si = TMS, R4,R5 = But) and -diazo phosphonothioic diamides (X = S, R1,R2,R3 = TMS, R4,R5 = NPr2i ) were obtained by direct sulfurization of the corresponding phosphanyl precursors .

N2

S

PEt2

P(X)R4R5

P(NPr2i )2

PhN

N2

GeEt3

SiR1R2R3

267

GeEt3

268

269

R1R2R3Si = TMS, TBDMS, SiPr3i , SiPh3 R4, R5 = alkyl, dialkylamino, OMe, OEt X = lone pair, O, S Cl + P(NPr2i )2

M1Me3 N2

N2 BR – 3

270

M2Me3

M1 = Si, Ge M2 = As, Sb, Bi

271

Figure 13

(ii) Germanium derivatives Insertion reaction of phenyl isocyanide into the weak Ge
P bond of germanylphosphine (Et3GePEt2) led to the formation of triethylgermanium derivative 268 (Figure 13). The -diazo phosphonothioic diamide triethylgermanium compound 269 was obtained by reacting lithiated -diazo phosphonate with trialkylgermanium chloride .

(iii) Boron derivatives The only examples of this class are internal salts 270 (R = H, F) which can be prepared by oxidative ylidation of the -diazophosphane 267 (X = lone pair, R1,R2,R3Si = TMS, R4,R5 = NPri2) with CCl4 followed by reaction with boron-containing Lewis acids (BH3 or BF3) (Figure 13) . Since the publication of chapter 6.21.2.2.1 no new synthetic methods for these classes of iminocarbonyl derivatives have been described.

6.21.2.2.2

Iminocarbonyl derivatives with one As, Sb, or Bi function and one Si, Ge, or B function

The reaction of (TMS)diazomethanes (M1 = Si) with metal amides (M2 = As, Sb, Bi, R = Me, n = 3) leads to the formation of the corresponding (-diazo(TMS)methyl)dimethyl arsines, stibines, and bismuthines 271 (Figure 13). (Diazotrimethylgermanylmethyl)dimethylarsine (M1 = Ge, M2 = As, R = Me, n = 3) can be prepared similarly . No new synthetic methods for these classes of iminocarbonyl derivatives have been described since the publication of chapter 6.21.2.2.2 .

652

Functions Containing an Iminocarbonyl Group

6.21.2.3

Iminocarbonyl Derivatives with One P, As, Sb, and Bi Function and One Metal Function

6.21.2.3.1

Iminocarbonyl derivatives with one P function and one metal function

(i) Main group metals Metallation of the phosphinodiazomethane derivatives with BuLi gives corresponding lithium salts 272 (Figure 14). Treating the diazolithium salt 272 with trimethylchlorostannane provides the diazomethylstannyl compound 273 .

P(X)(NPr2i )2

P(X)R1R2

P(O)R1R2

N2

N2

N2 SnMe3

Li

272

Ag

273

277

X = O, lone pair R1, R2 = But, NPr2i

P(O)R1R2

AsMe2

N2

N2

MMe3

N2

Hg

N2

Hg N2

AsMe2

P(O)R1R2

AsMe2

281

279 M = Sn 280 M = Pb

278

Figure 14

In 1995, from the reaction of lithium salt of [bis(diisopropylamino)phosphine]diazomethane with triphenyl- and tricyclohexylchlorostannane, the diazo derivatives 274 were obtained . Photolysis of these compounds in the presence of t-butyl isocyanide afforded ketene imines 275 as depicted in Scheme 69. The reaction proceeds via rather unstable (phosphino) (stannyl)carbene which can be trapped by t-butyl isocyanide. Compounds 275 can easily be isolated after treatment with elemental sulfur, as the compounds 276 in 86–88% yield.

PR2 N2

hν R2P C SnR13

SnR13 274

But–NC

S8

R2P N R13Sn

R = Pr2i N; R1 = Ph, cyclohexyl

But 275

S R2 P N R13Sn

But 276

Scheme 69

(ii) Transition metals Metallation of the phosphinediazomethane derivatives with Ag2O or Ag(acac) and HgO or Hg(acac)2 led to the formation of diazomethylsilver (277, R1 = R2 = OMe, OEt, R1 = OMe, R2 = Ph) and bis-(diazomethyl)mercury, respectively (278, R1,R2 = OMe, OEt, Ph) (Figure 14) . No new synthetic methods for this class of iminocarbonyl derivatives have been described since the publication of chapter 6.21.2.3.1 in .

653

Functions Containing an Iminocarbonyl Group 6.21.2.3.2

Iminocarbonyl derivatives with one As, Sb, and Bi function and one metal function

Metallation of diazomethylarsines with metal amides Me3SnMe2 and Me3PbN(TMS)2 provides the corresponding derivatives 279 and 280 with trimethylstannyl and trimethylplumbyl substituents, respectively (Figure 14). Similarly, using Hg(N(TMS)2)2 as metallating agent, bis-(diazo(dimethylarsino)methyl)mercury 281 is obtained . Since the publication of chapter 6.21.2.3.2 in no advances have occurred in this area.

6.21.2.3.3

N-Unsubstituted iminocarbonyl derivatives

Although the electronic structure of HN=C(TMS)2 has been calculated, synthetic method for this class of iminocarbonyl derivatives is not reported .

6.21.2.3.4

N-Alkyl- and N-aryliminocarbonyl derivatives

There were two general methods described in chapter 6.21.3.1.2 in . First one, consisting in the insertion reaction of alkyl or aryl isocyanides into metal–metal bonds. The N-cyclohexyl derivative 282 (Figure 15) was prepared by insertion of N-cyclohexyl isocyanide into the Si
Si bond of a disilane in the presence of Pd(0) or Pt(0) as a catalyst. The Pd(0)-catalyzed method was further used to synthesize a wide range of N-aryl analogs.

Me N R1R2R3Si

R SiR1R2R3

N2

SiR1R2R3

TMS

282

R1

N

Me

287

283

R = cyclohexyl, aryl

R2

SiR1R2R3 = TMS, TBDMS

Figure 15

The second method is based on a transmetallation reaction and can be applied to the synthesis of (2,6-xylimino)bissilanes 283 (Figure 15). This compound is obtained from (2,6-xylimino) (TMS)methyllithium by treatment with requisite chlorosilane. In 1994 the regioselective functionalization of bis-(trimethylsilyl)methylimines with electrophiles was described . Thus, silylated azomethines 284 are readily deprotonated in THF at
78  C to give the 2-azaallyllithium compounds 285, which react further with electrophilic reagents to give functionalized silylated imino derivatives 286 (Scheme 70).

R N H

SiMe3 SiMe3

Base

R

THF, –78 °C to rt

H

R1Cl

N Li

+

284

SiMe3

R H R1

N

SiMe3

SiMe3 SiMe3

285

286 t

Base = MeLi or LIDAKOR (the superbasic mixture of LIDA /Bu OK) R = Ph, alkenyl; R2 = Me3Si, COOEt

Scheme 70

654 6.21.2.3.5

Functions Containing an Iminocarbonyl Group N-Haloiminocarbonyl derivatives

Electronic structures of the imines HalN = C(TMS)2 have been calculated, but no synthesis of this class is reported in the literature .

6.21.2.3.6

N-Aminoiminocarbonyl (diazomethane) derivatives

The following methods were described in chapter 6.21.3.1.4 in . Silylated and germylated lithiodiazomethanes undergo transmetallation reaction upon treatment with chlorosilanes and chlorogermanes to give bis(silyl)diazomethanes (287, R1 = TMS, (TMS)SiMe2, (TMS)3Si), and bis(germanyl)diazomethanes (287, R1 = R2 = GeMe3), respectively (Figure 15). Another method for preparation of these compounds involves the transfer of the diazo group from tosyl azide to the carbanion derived from bis(TMS)- or bis(germyl)methanes. In 1995 the bis(silyldiazomethyl)polysilanes 288 were prepared by lithiation of silyldiazomethane followed by coupling with the corresponding dichloropolysilanes (Figure 16) .

N2 Me N2 C Si C SiMe2R Me n

RMe2Si

288

A, n = 2, R = Me

MeMe Si Si MeMe

C, n = 3, R = Me

Me Ph Me Si Si Si Me Ph Me

B, n = 3, R = Ph

MeMe Me Si Si Si MeMe Me

D, n = 4, R = Ph

MeMe Me Me Si Si Si Si MeMe Me Me

Figure 16

Diazogermylenes 289 were obtained in good yields by one-pot synthesis as described in Scheme 71 . These compounds were found to be promising precursors to Ge
C triple bonds (germynes).

ArBr

nBuLi

ArLi

GeCl2

ArGeCl

N2 ArGe C SiMe3

THF/C6H14

THF

THF

Me3SiC(N2)Li

289 Ar = 2,6

1 (R 2NCH2)2C6H3 i

R1 = Et, Pr

Scheme 71

6.21.2.3.7

N-Silyliminocarbonyl derivatives

N-silylated bis-(TMS)imines 290 (Figure 17) are formed as side products in the reaction of silaethene with silyl azides (RN3). Since the publication of chapter 6.21.3.1.5 no advances have occurred in this area.

655

Functions Containing an Iminocarbonyl Group

TMS 3

RN

SnR13

N

R N TMS

290

Me

SiMe2R2

291

Me Cu

SiR3

292

R = TMS, (TMS)2NSiMe2

Figure 17

6.21.2.4

Iminocarbonyl Derivatives with One Metalloid Function and One Metal Function

6.21.2.4.1

N-Alkyl- and N-aryliminocarbonyl derivatives

These compounds bear resemblance to the iminocarbonyl derivatives with two metalloid functions, and are prepared in a similar manner either by insertion of alkyl and aryl isocyanides into metal–metal bonds or by transmetallation reactions . Thus, the Pd(0)catalyzed insertion of isonitriles into Si
Sn bond of organosilylstannanes leads to the formation of organosilyl(N-alkylimino)stannanes (291, R1,R2 = Me, R3 = Pri, C6H11, C6H13, 2-MeC6H4; R1 = Me, R2 = But, R3 = Pri; R1 = Me, R2 = But, R3 = Pri). (2,6-Xylimino) (TMS)methyllithium has been converted into copper reagents 292 by transmetallation reaction with CuBrSMe2 or Cu acetylide (Figure 17) . Recently, Xue and co-workers have studied in detail the insertion reactions of aryl isocyanides into the zirconium alkyl silyl complexes (293, R1,R2,R3 = bn) and amido silyl complexes (293, R1,R2,R3 = Me2N, R1,R2 = Me2N, R3 = (Me3Si)2N) . In case of alkyl silyl complexes the isocyanide insertion occurred exclusively into the Zr
Si bond to give the product 296 as a result of silyl ligand migration (Scheme 72). Alternatively, the amido silyl complexes containing different ligands offered the opportunity to observe the competition between silyl and amido ligands in the migration step and to study whether silyl or amido ligand migration is preferred. It was found that arrangement of ligands in 293 directs the attack of the isocyanide molecule. Thus, in amido silyl complex (Me2N)3ZrSi(SiMe3)3 the trans attack to the silyl ligand results in the formation of 242. However, in case of (Me2N)2[(Me3Si)N]ZrSi(SiMe3)3, steric hindrance causes the isocyanide attack to take place cis to the silyl ligand with formation of 294 where only amide migration is feasible giving rise to the formation of 296.

6.21.2.4.2

N-Aminoiminocarbonyl (diazomethane) derivatives

As described in chapter 6.21.3.2.2 in , these compounds are obtained by metallation reactions. Reaction of silyldiazomethanes with BuLi gives lithium silyldiazomethanides (297, SiR3 = TMS, tips, TMS-SiMe2). Treatment of (TMS)diazomethane with metal amides furnishes the plumbyl- and stannyl(TMS)diazomethanes 298. The stannyl(triisopropylsilyl)diazomethane 299 can be obtained from the reaction of bis(trimethylstannyl)diazomethane with Pri3SiCl. From the reaction of lithium silyldiazomethanide with Cl2Ni(PMe3)2 and Rh(PMe3)4Cl the (diazomethyl)trimethylsilanenickel(II) complex 300 and (diazomethyl)trimethylsilanerhodium(I) complex 301 were obtained, respectively (Figure 18). Since the publication of chapter 6.21.3.2.2 in no advances have occurred in this area.

6.21.3

IMINOCARBONYL DERIVATIVES CONTAINING TWO METAL FUNCTIONS

The only compounds of this class mentioned in chapter 6.21.4 in were the organometallic complexes with bridging isocyanide ligands.

656

Functions Containing an Iminocarbonyl Group Ar ArNC R1

Si(SiMe3)3 Zr 3 R R2

Zr

R1

R2

294

R1

Si(SMe3)3 Zr 3 R R2

R1, R2 = Me2N, R3 = (Me3Si)2N

Si(SiMe3)3 Zr R3

R

R2

R3

R1, R2, R3 = bn

ArNC

1

Si(SiMe3)3

296

Isocyanide attack cis to the silyl ligand

293

C

N

Ar

N

R1

C Zr

R3

Si(SiMe3)3

C N Ar

R2

295

242

Isocyanide attack trans to the silyl ligand

R1, R2, R3 = Me2N

Scheme 72

SnMe3

SiR3

SiR3

N2

N2

N2

SiPri3

MMe3

Li

M = Sn, Pb 297

298

TMS N2

299

TMS PMe3 Rh PMe3 Me3P PMe3

N2

PMe3

Ni Me3P Cl

300

301

Figure 18

Iminocarbonyl derivatives 302 in which a C¼N double bond is bound to two Al atoms with very short Al
N bond are formed by the insertion of isonitriles into the Al
Al bond (Equation (30)) .

(Me3Si)2HC CH(SiMe3)2 Al Al CH(SiMe3)2 (Me3Si)2HC

i

(Me3Si)2HC Al (Me3Si)2HC

R N

302 i. RCN, n-pentane, –25 °C to rt, 1 h R = CMe3, Ph

CH(SiMe3)2

ð30Þ

657

Functions Containing an Iminocarbonyl Group

Other interesting examples of the complexes 303 which contain two different metals bound to the iminocarbonyl group are obtained by insertion of MeNC into the polar M1
M2 bonds, as shown in Equation (31) . Me2 Si

Me2

Tol N Me2

Me Si Si Si Me2

Cp M

N N

Tol

M1(CO)2 Tol

Si MeNC Me Si Si Si

M

Tol Me

N Me2 N N

Me2 303

N M Tol Tol

M1(CO)2 Cp

M1

Ti

Fe

Ti

Ru

Zr

Fe

Zr

Ru

Hf

Fe

Hf

Ru

ð31Þ

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660

Functions Containing an Iminocarbonyl Group Biographical sketch

Franciszek Sa˛czewski was born in Sopot, Poland on November 18, 1951. He graduated from Medical University of Gdan´sk in 1974 with M.S. degree in pharmacy and that same year began his career at the Department of Organic Chemistry. In 1981 he received his Ph.D. and in 1988 D.Sc. degree in pharmaceutical chemistry, and in 1999 was promoted to full professor. During 1983–1984 and 1988–1989 he was working with Prof. Alan Roy Katritzky at the Department of Chemistry, University of Florida, USA. He is a member of the Royal Society of Chemistry (UK), International Society of Heterocyclic Chemistry, Polish Pharmaceutical Society, and Polish Chemical Society. Prof. F. Sa˛czewski is currently the head of the Department of Chemical Technology of Drugs, Medical University of Gdan´sk, Poland. His research interests include the design and synthesis of nitrogen-containing heterocyclic compounds with potential circulatory, anticancer, and antiHIV activities.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 605–660

6.22 Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal V. D. ROMANENKO and V. L. RUDZEVICH National Academy of Sciences of Ukraine, Kiev, Ukraine 6.22.1 FUNCTIONS CONTAINING DOUBLY BONDED P, As, Sb, or Bi 6.22.1.1 General Remarks 6.22.1.2 Dicoordinate Phosphorus and Arsenic Derivatives 6.22.1.2.1 Dihalomethylenephosphines, Hal2C¼PY 6.22.1.2.2 Oxygen- and sulfur-substituted methylenephosphines, RO(X)C¼PY and RS(X)C¼PY 6.22.1.2.3 Nitrogen-, phosphorus-, and arsenic-substituted methylenephosphines, R2E(X)C¼PY (E = N, P, As) 6.22.1.2.4 Silicon- and germanium-substituted methylenephosphines, R3Si(X)C¼PY and R3Ge(X)C¼PY 6.22.1.2.5 Metallated methylenephosphines, LnM(X)C¼PY 6.22.1.2.6 C,C-diheterosubstituted methylenearsines, X2C¼AsY 6.22.1.3 Tricoordinate Phosphorus Derivatives 6.22.1.3.1 Stabilized [X2C¼PY2]+ species 6.22.1.3.2 Functions with a phosphorus–metal
-donor bond, X2C¼P(MLn)Y 6.22.1.3.3
35-Methylenephosphoranes, X2C¼P(¼Z)Y 6.22.1.4 Tetracoordinate Phosphorus Derivatives 6.22.1.4.1 Dihalosubstituted ylides, Hal2C¼PY3 6.22.1.4.2 Oxygen-, sulfur-, and selenium-substituted ylides, RE(X)C¼PY3 (E = O, S, or Se) 6.22.1.4.3 Nitrogen-, phosphorus-, arsenic-, and antimony-substituted ylides, R2E(X)C¼PY3 (E = N, P, As, or Sb) 6.22.1.4.4 Silicon-, germanium-, and boron-substituted ylides, R3E(X)C¼PY3 (E = Si or Ge) and R2B(X)C¼PY3 6.22.1.4.5 Metal-substituted ylides, LnM(X)C¼PY3 6.22.1.5 Tetracoordinate Arsenic, Antimony, and Bismuth Derivatives 6.22.1.5.1 C,C-Diheterosubstituted arsonium ylides, X2C¼AsY3 6.22.1.5.2 Stibonium and bismuthonium ylides bearing heterosubstituents, X2C¼EY3 (E = Sb or Bi) 6.22.2 FUNCTIONS CONTAINING A DOUBLY BONDED METALLOID 6.22.2.1 Tricoordinate Silicon and Germanium Derivatives 6.22.2.1.1 Diheterosubstituted silaethenes, X2C¼SiY2 6.22.2.1.2 C,C-Diheterosubstituted germaethenes, X2C¼GeY2 6.22.2.2 Functions Incorporating a Doubly Bonded Boron 6.22.2.2.1 Methyleneboranes, X2C¼B-Y 6.22.2.2.2 2-Borataallenes, [X2C¼B¼CY2]
6.22.3 FUNCTIONS INCORPORATING A DOUBLY BONDED METAL 6.22.3.1 Transition Metal–Carbene Complexes 6.22.3.1.1 N-Heterocyclic carbene complexes 6.22.3.1.2 Silicon-substituted carbene complexes, R3Si(X)C¼MLn 6.22.3.2 Functions with a Formal Tin–Carbon and Lead–Carbon Double Bond

661

662 662 662 662 664 665 668 671 673 675 675 676 677 680 680 681 681 685 686 687 687 687 688 688 688 691 693 694 695 695 696 696 702 704

662 6.22.1

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal FUNCTIONS CONTAINING DOUBLY BONDED P, As, Sb, or Bi

6.22.1.1

General Remarks

This section will survey the chemistry of functions X1X2C¼E (X1, X2 = heteroatom substituents; E = P, As, Sb, or Bi) featuring a double bond between carbon and the heavier group 15 element. The known structural types of molecules containing these functions, arranged with increasing coordination number of element, are listed below. It is the peculiar -bonding situation inducing a trigonal planar coordination around carbon which justifies the description of compounds A–C as heteroatom analogs of alkenes (Figure 1). In contrast, the compounds of the type D contain the highly polarized C

E+ bond and can be considered either as ylides or as element-stabilized carbene species.

X1

X1 E X2

Y A

X2

Y E Y

+

B

X1

Z

X1

Y

X2

E X2 C

Y E Y Y D

Figure 1 Heteroatom analogs of alkenes.

6.22.1.2

Dicoordinate Phosphorus and Arsenic Derivatives

This section concerns compounds of the type X1X2C¼EY (E = P, As) with three heteroatom– carbon bonds, whatever the nature of substituent on the phosphorus or arsenic. Since the publication of chapter 6.22 in COFGT (1995) , the synthetic chemistry of phosphaalkenes and arsaalkenes has advanced dramatically. While no single review dealing specifically with C,C-diheteroatom-substituted derivatives has been published, related surveys have appeared. The most important of these are by Dillon and co-workers , Weber and co-workers , Mackewitz and Regitz , Yoshifuji , and Denis and Gaumont . There have been no experimental reports as yet of C,C-diheterosubstituted stiba- and bismaalkenes of the type X1X2C¼EY (E = Sb, Bi).

6.22.1.2.1

Dihalomethylenephosphines, Hal2C¼PY

A variety of routes developed for the synthesis of these compounds is presented in Scheme 1. By far the most general synthetic strategy involves the base-induced dehydrohalogenation of dihalomethylchlorophosphines (route ‘‘a’’). This method, as well as the dehalogenation of trihalomethylchlorophosphines (route ‘‘b’’), has become standard procedure for C,C-dihalophosphaalkene production. In addition, the dehydrohalogenation of trihalomethylphosphines (route ‘‘c’’) and the thermolysis of trifluoromethyl(stannyl)phosphines (route ‘‘d’’) also provide dihalomethylenephosphines. It has to be pointed out that in contrast to the usual procedures in olefinic chemistry, only dehydrohalogenation or dehalogenation of sterically crowded phosphine precursors allows the isolation of monomeric phosphaalkenes. Although electronic factors are not totally negligible, steric factors are of primary importance for the kinetic stabilization of dihalomethylenephosphines . Ab initio molecular orbital calculations have been applied to determine the fluorine effect on the stability of phosphaalkene F2C¼PF and its energetically low-lying rearranged isomers FC– PF2 (‘‘phosphinocarbene’’) and F3C–P (‘‘alkylphosphinidene’’). The phosphaalkene was shown to be the most stable isomer; its energy differs from that of the phosphinocarbene by 161 kJ mol
1 . The kinetically stabilized C,C-difluorophosphaalkenes are normally prepared by gas-phase thermal Me3SnF elimination starting from F3C(R)PSnMe3 . Like alkenes, fluorine containing phosphaalkenes have a marked potential for undergoing cycloaddition reactions and, in view of the variety of 1,2- and 1,3-dipoles available, they widen the scope of the phospha-heterocycle synthesis enormously .

663

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal Hal a Hal

b

Hal

YLi

PCl2

Hal4C/R3P

Cl P Y

–LiCl

Hal

YPHal2

Hal Hal3C P Y

–R3PHal2

B –B.HCl

R3P or BuLi –R3PHal2 or –BuHal, –LiHal

Hal Hal

c

d

H Hal3C P Y

YP(Li)H Hal4C

–LiHal

Cl F3C P Y

B . –B HHal

SnMe3 F3C P Y

Me3SnLi –LiCl

P Y

–Me3SnF

Y = preferably Alk, Ar, or R2N (routes "a", "b"), Ar (route "c"), F3C (route "d") R = preferably But or Et2N; B = DBU or Et3N

Scheme 1

Experimental details for the preparation of phosphaalkene 3 are described in Synthetic Methods of Organometallic and Inorganic Chemistry . Refluxing a solution of CHCl3, PCl3, and AlCl3 followed by treatment with MeOPCl2 gave dichloromethyl derivative 1 which on treatment with Mes*Li (Mes* = 2,4,6-tri-t-butylphenyl) gave the compound 2. The final conversion of 2 into phosphaalkene 3 has been accomplished through dehydrochlorination with DBU (Scheme 2).

CHCl3

+

i. AlCl3 ii. MeOPCl2

PCl3

Cl

Cl

Mes*Li –LiCl

P Cl

Cl

1 (42%) Cl Cl

Cl P Mes*

DBU/ THF –DBU.HCl

2

Cl Cl

P Mes*

3 (72%)

Mes* = 2,4,6-tris(t-butyl)phenyl

Scheme 2

Dillon and Goodwin have been able to prepare the phosphaalkene Cl2C¼PArf (Arf = 2,4,6tri-trifluoromethylphenyl) using a similar approach. The precursor phosphine Cl(Cl2CH)PArf was prepared by two procedures, either directly by the action of ArfPCl2 on CHLiCl2, or via the corresponding organocadmium reagent . The dehalogenation route has also received further attention. A range of new phosphaalkenes including the compounds 4–6 bearing very bulky groups has been prepared in recent years by Escudie´ and co-workers . A variant of dehalogenation reactions should be mentioned which permits sterically crowded bis(trichloromethyl)phosphines (Cl3C)2PR (R = Mes or 2,2,6,6-tetramethylpiperidino) to be converted into phosphaalkenes 7 and 8 using (Et2N)3P . In addition, further study has appeared of generation of the thermally unstable phosphaalkene Cl2C¼PCl . Also reported in this study is a synthesis of the phosphaalkene precursor Cl2CHPCl2 from Cl2CHZnCl and PCl3.

664

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal Cl

Cl

Cl P

Ar

P

P

Cl Ar

Cl

Cl

8

7

4, Ar = Mes

N

5, Ar = p-MeOC6H4 6, Ar = p-MeC6H4

The importance of steric protection for the stability of C,C-diiodophosphaalkenes, I2C¼PR, was investigated by varying the size of group R. The phosphaalkene I2C¼P-Is (Is = 2,4,6Pri3C6H2) could be prepared in 15% isolated yield by reaction of IsPCl2 and CHI3 with 2 equiv. of LDA, in analogy to the synthesis of the stable, sterically more protected I2C¼PMes* (Mes* = 2,4,6-But3C6H2). If the steric protection on the phosphorus was decreased further (R = Es = 2,4,6-Et3C6H2, R = Mes = 2,4,6-Me3C6H2), the substituted phosphines RP(Cl)NPri2 (R = Es, Mes) were formed as main products, in addition to thermally unstable phosphaalkenes I2C¼P-Es and I2C¼P-Mes. The reaction of I2C¼P-Mes* with bromine gave an (E)/(Z) mixture of the C-bromo-C-iodophosphaalkene Br(I)C¼P-Mes*. Further reaction with bromine proceeded via Br2C¼P-Mes* and finally led to Br(Br2CH)P-Mes* .

6.22.1.2.2

Oxygen- and sulfur-substituted methylenephosphines, RO(X)C¼PY and RS(X)C¼PY

Among the most common routes for the synthesis of these compounds are those based on elimination and silyl migration reactions (Equations (1) and (2)) . RX

Cl P Y

RX

1,2-Elimination

RX

–HCl

RX

P Y

ð1Þ

P Y

ð2Þ

X = O, S

X

TMS P Y

RX

1,3-Me3Si shift –HCl

TMS X RX

X = O, S

In an interesting extension of the 1,2-elimination methodology, it has been found that lithium bis(trimethylsilyl)phosphide reacts with an excess of dimethyl carbonate to afford the bis(1,2dimethoxyethane-O,O0 )lithiooxymethylidynephosphine 10. The phosphaalkene 9 is probably an intermediate in this reaction but it has not been detected directly (Scheme 3) . MeO (TMS)2PLi

O

+ MeO

DME, –20 °C

(TMS)2P

OMe

LiO

OMe

LiO P MeO

TMS 9

–MeO–TMS 79%

Scheme 3

LiO C P.2DME

–MeO–TMS

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

665

The silatropic principle combined with the insertion reaction has been used to prepare the rather unstable metallophosphaalkenes 11, which decomposed to the doubly metallated 1,3,4thiadiphospholes by extrusion of (TMS)2S. However, the compounds 11 were intercepted as isolable [(CO)5Cr]-adducts 12 by treatment with [(Z)-cyclooctene]Cr(CO)5 (Scheme 4) .

[M]-P(TMS)2

CS2

TMS S

Pentane, rt

TMS S

P [M]

LCr(CO)5

TMS S

Benzene, rt

TMS S

Cr(CO)5 P [M] 12

11 [M] = Cp*(CO)2M; M = Fe, Ru

M = Fe (40%)

L = (Z )-cyclooctene

M = Ru (32%)

Scheme 4

Yoshifuji and co-workers utilized an in situ generation-capture methodology for the synthesis of phosphaalkenes (Z)-14 and 15 via reaction of the C,C-dibromophosphaalkene 13 with butyllithium and diphenyldisulfide (Scheme 5) . This development was the key to further applications of the sulfur-substituted phosphaalkenes . Br Br

P Mes*

i, ii

PhS

55%

Br

13

P Mes*

i, ii

PhS

51%

PhS

Z-14

P Mes* 15

i. BunLi, THF, –100 °C; ii. PhSSPh, THF, –78 °C to 0 °C

Scheme 5

6.22.1.2.3

Nitrogen-, phosphorus-, and arsenic-substituted methylenephosphines, R2E(X)C¼PY (E = N, P, As)

(i) From C,C-dihalomethylenephosphines A kinetically stabilized phosphanylidene carbenoid (Z)-16 was prepared from the phosphaalkene 3 and butyllithium (vide infra), and was allowed to react with Ph2PCl to afford the corresponding 2-chloro-1,3-diphosphapropene (Z)-17 in good yield (78%) after silica-gel column chromatographic purification. Similarly, starting from (E)-16 and Ph2PCl, an attempt was made to synthesize (E)-17. Although NMR signals due to (E)-17 were observed in the reaction mixture, the latter was isomerized to (Z)-17 after the usual work-up procedure. The treatment of (Z-)17 with [W(CO)5(THF)] leads to the complex (Z)-18 with the metal carbonyl group at the less hindered phosphorus atom (Scheme 6) . Of the compounds of the type Hal(R2As)C¼PY, up to now 19 has been isolated from the reaction of 1-bromo-2-phosphaethenyllithium with Mes*AsF2 (Scheme 7). Further addition of nbutyllithium to 19 at
90  C led to the organolithium intermediate, which lost LiF to give in nearly quantitative yield the arsaphosphaallene Mes*-As¼C¼P-Mes* .

(ii) Synthesis by condensation reactions The starting point for the now extensive chemistry of the C,C-bis(dialkylamino)methylenephosphines was the synthesis of (R2N)2C¼P-TMS via the condensation of (TMS)3P with (R2N)2CF2 . The generality of this approach is restricted, however, by possible difficulty in the preparation of the requisite geminal difluorides . An alternative route to the phosphaalkene 20a is provided by the reaction of S-methyl

666

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

Li P Mes*

Cl

Ph2P

Ph2PCl 78%

Cl

P Mes*

39%

(Z )-17

(Z )-16

Cl

(Z )-18

Cl

Ph2PCl

P Mes*

Li

W(CO)5 Ph2P P Cl Mes*

W(CO)5(THF)

Ph2P

(E )-16

P Mes*

(E )-17

Scheme 6

BunLi

Li

Et2O, –100 °C

Br

Br Br

P Mes*

F Mes* As

Mes*AsF2

P Mes*

27%

Br

13

P Mes*

19

Scheme 7

bis(dimethylamino)thiouronium iodide with lithium bis(trimethylsilyl)phosphide (Equation (3)). Spontaneous condensation occurred upon mixing of equimolar amounts of the reagents in a mixture of pentane and 1,2-dimethoxyethane . -X+ Me2N SMe

I–

Me2N

(TMS)2PLi.DME

Me2N

–LiI, –MeS–TMS, –DME 73%

Me2N

P

ð3Þ TMS

20a

(iii) Synthesis via free carbenes It has been demonstrated that N-heterocyclic carbenes are sufficiently nucleophilic to depolymerize cyclopolyphosphines such as (PPh)5 and (PCF3)4 and produce compounds of the type 21, which can be formulated either as phosphaalkenes or as carbene–phosphinidene complexes (Equation (4)) . The latter formulation is favored by the observation that treatment of the compounds 21 with boranes results in the formation of P,P-bis(borane) complexes, indicating the availability of two lone pairs at phosphorus .

R2

R1 N

R2

N R1

+

1/x (R3P)x

THF, rt

R2

R1 N

R2

N R1

R2 P R3

R2

21a–21c 21

R1

R2

R3

a

Me

Me

Ph

b

Mes

H

Ph

c

Mes

H

CF3

R1 N – + P N R3 R1

ð4Þ

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

667

It is also possible to prepare bis(amino)phosphaalkenes by direct reaction of a nucleophilic carbene with dichlorophenylphosphine. This approach is illustrated in Equation (5) for the saturated 1,3-dimesitylimidazolin-2-ylidene . The generality of this methodology is restricted, however, by difficulties in the preparation of the starting carbene. Mes N

Mes N

2

+

PhPCl2

+

P THF, rt, 1 h

N Mes

69%

Mes N+ Cl N Mes

N Ph Mes

Cl–

ð5Þ

(iv) Derivatization of P-hydrogen- and P-silyl-methylenephosphines P-Hydrogen- and P-silyl-substituted phosphaalkenes of the type R2N(Y)C¼PX (X = H, TMS) are important reagents for the introduction of R2N(Y)C¼P groups into organic molecules via electrophilic substitution at the dicoordinated phosphorus atom. In particular, treatment of the easily accessible phosphaalkene Et2N(F)C¼PH ((E)/(Z) = 18/82) with halophosphines and haloarsines in the presence of triethylamine as base provides a route to the P-phosphino and Parsino derivatives Et2N(F)C¼P-ER2 (E = P, As) . 1-Diethylamino-1-fluoro-2phosphaalkenes of the type Et2N(F)C¼P-ER3 [R3E = TMS, Me3Ge, (F3C)3Ge and Me3Sn) are prepared in moderate yields by reaction of Et2N(F)C¼PH with R3EX (X = Cl, I). The relatively stable derivative Et2N(F)C¼P-TMS was used as a substrate for reactions with pivaloyl, adamantoyl, and benzoyl chloride, respectively, which by cleavage of the Si–P bond yield the ‘push/pull’ phosphaalkenes Et2N(F)C¼P-C(O)R (R = But, Ad, Ph) . Similarly the phosphaalkene 20a was transformed into the P-acyl derivatives (Me2N)2C¼PC(O)R (R = But, Ph) when allowed to react with an equimolar amount of pivaloyl or benzoyl chloride . The phosphaalkenyl functionalized carbyne complexes 23 have been obtained by reacting the chlorocarbyne complexes 22 and P-silylated phosphaalkenes 20 (Equation (6)) . The reaction of 20 with Cp*(CO)2MBr (M = Fe, Ru) in hydrocarbon solvents at room temperature affords moderate yields of the metallophosphaalkenes 24 (Equation (7)) . R2N

R2N +

P

Cl

C

M(CO)2Tp'

TMS

R2N

P –TMS–Cl

R2N

C M(CO)2Tp'

22

20a, b

ð6Þ

23

Tp' = HB(3,5-Me2C3HN2)3; M = Mo, W; R = Me (a), Et (b)

R2N

R2N P R2N

+ TMS

OC

M

Br CO

20a, b

32–69%

R2N

P M OC CO

ð7Þ

24

M = Fe, Ru; R = Me (a), Et (b)

(v) Miscellaneous C-Phosphino-phosphaalkenes 25 are formed in the thermal ring opening of diphosphiranes, a theoretical study suggesting the intermediacy of diradical species . In the presence of either boron trifluoride or triflic acid, the diphosphapropene 26 gives the diphosphaallylic cation 27, which is then transformed into the four-membered ring system 28. In the presence of a base, the latter converts to the three-membered system 29 .

668

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

R2N P P

P Mes* R2N

Cl 25

NR2

NR2

+

(R2N)2P

R2P

P

P NR2

R2N

NR2

26

27

+

N R

P NR2

NR2

+

P P

NR2

R 28

29

On heating in toluene the 1,3-diphosphacyclobutane-2,4-diyl 30 isomerizes by cleavage of the P
C bond to give the diphosphapropene 32. A plausible intermediate of this reaction is the phosphinocarbene 31, which results from a ring opening and stabilizes by CH activation of an ortho-positioned t-butyl group to give 32 (Scheme 8) . Cl X Mes* P

P *Mes X Cl

Toluene, 100 °C

P

P *Mes

Mes* P Cl

H Cl

Me Me

31

30

Mes* P

Cl

Cl

32

Scheme 8

6.22.1.2.4

Silicon- and germanium-substituted methylenephosphines, R3Si(X)C¼PY and R3Ge(X)C¼PY

The heavier group 14 elements, especially silicon, exert a stabilizing effect on the methylenephosphine function and consequently numerous C-silyl-substituted phosphaalkenes have been synthesized and thoroughly studied. The development of C-germylated phosphaalkenes has proceeded at a slower pace and has not yet reached the degree of complexity of its silicon counterparts. However, in the 1990s a range of C-germyl-substituted phosphaalkenes has become available, and recent works have demonstrated that many of these compounds exhibit excellent thermal stability.

(i) From C,C-dihalomethylenephosphines A halogen–metal exchange/coupling route is the most effective for the preparation of highly functionalized phosphaalkenes R3E(Hal)C¼PY (E = Si, Ge) as it permits a chemical variation of the substituent pattern with retention of the P¼C unit. Several examples of the use of this strategy have been reported. For example, addition of n-butyllithium to the phosphaalkene 13 at low temperature with subsequent quenching the resulting lithio derivative with chlorotrimethylsilane furnished (Z)-33 in 98% isomeric purity . Conversion of the phosphaalkene (Z)-33 to the corresponding lithio derivative with n-butyllithium, followed by the addition of 1,2-dibromoethane produced the silylated species (E)-33 as the only isomer (Scheme 9) . A similar approach has been used for the preparation of C-germyl substituted phosphaalkene 34. The best yield in 34 was obtained when the reaction mixture was stirred for 1 h at
80  C, after addition of the difluorogermane to 13 at
100  C. The phosphaalkene 34 can also be obtained in one pot by adding 2 equiv. of BunLi to a mixture of 13 and Mes2GeF2 in Et2O since at
120  C butyllithium does not react with the Ge
F bond of difluorodimesitylsilane (Equation (8)) .

Br Br

P Mes* 13

i. BunLi ii. TMS-Cl –130 °C

i. BunLi TMS Br

P Mes*

(Z )-33 (90%)

Scheme 9

ii. BrCH2CH2Br

Br

THF, –110 °C

TMS

P Mes*

(E )-33 (60%)

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal i. BunLi ii. Mes2GeF2

Br P Mes*

Br

13

669

F Mes2Ge

ð8Þ

P Mes*

Et2O, –100 °C 35%

Br 34

The carbenoid Cl(Li)C¼PMes*, which is much more stable than its bromo analog, has also been shown to behave as a nucleophile when treated with halogermanes. Thus, reaction of 2-phosphaethenyllithium with difluoro(mesityl)(fluorenyl)germane afforded the fluoro(germyl)phosphaalkene 35 in 77% yield. In contrast, the chloro analog 36 was obtained only in very low yield (10%). However, the phosphaalkene 36 could be prepared in good yield by a two-step procedure involving the prior reaction of the carbenoid Li(Cl)C¼P-Mes* with trichloromesitylgermane, followed by the addition of fluorenyllithium . As a further development of this work the synthesis of germylphosphaalkene 38 has been achieved starting from dichlorophosphaalkene 3 and difluorogermane 37 (Scheme 10) .

i. BunLi ii. Mes(R2CH)GeX2

Cl P Mes*

Cl

X Mes Ge R2HC P Cl Mes*

THF, –78 °C

3

35, X = F 36, X = Cl

i. BunLi ii. MesGeCl3

Tip(But)GeF2

R2CHLi

THF, –78 °C

37 Tip But Ge F P Cl Mes*

Mes Cl2Ge P Mes*

Cl

38 ; Tip = 2,4,6-Pr3i C6H2; Mes* = 2,4,6 = Bu3t C6H2

R2CH =

Scheme 10

(ii) By elimination reactions An example from recent literature includes an improved procedure for the preparation of Pchloro-bis(TMS)methylenephosphine 39 (Scheme 11) .

TMS Cl TMS

i. Mg ii. PCl3

TMS

Et2O/THF

TMS

PCl2

Et3N

TMS

Et2O, rt 70%

TMS

P 39

Scheme 11

Cl

670

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

(iii) By derivatization of P-halo-C,C-bis(TMS)methylenephosphines A very useful technique for the direct introduction of the (TMS)2C¼P moiety into a variety of molecules is based on the nucleophilic substitution at the dicoordinated phosphorus atom. Phosphaalkenes (TMS)2C¼P-Y (Y = Hal, TfO) are particularly useful for the creation of new phosphorus–carbon and phosphorus–heteroatom bonds. The nucleophiles more commonly employed are Grignard and organolithium reagents as well as R2N, RO, RS
, and R2P
anions . However, progress has recently been made with functionalized nucleophilic species. Recent work has shown that 2,2-bis(TMS)-1-phosphaethenyl substituted pyridines 41 may be prepared by the reaction of lithium salt of the bifunctional carbanions 40 with phosphaalkene 39 (Equation 9) . TMS P TMS

R

+ Cl

R

R

N Li

Et2O, –78 °C

Li

39

TMS

R

N P

P

TMS

40

TMS

ð9Þ

TMS

rac/meso-41 R = Ph, TMS

Particular success was achieved using heteroatom nucleophiles as the substrates. Treatment of 39 with 2 equiv. of (TMS)2PLi in DME gave lithium salt of 1,2-diphosphapropenide 42 in 76% yield. Subsequent reaction of 42 with additional (TMS)2PLi provides a route to the 2,3,4-triphosphapentadienide system 43, an intermediate for the synthesis of heterocyclic phosphorus compounds . Reactions of equimolar amounts of (5-C5Me5)(CO)2Fe-E(TMS)2 (E = P, As) with 39 afforded the 1-metallo-1-phospha(arsa)-2-phosphapropenes 44 .

TMS

TMS TMS

P P

TMS

TMS

Li+(DME)

TMS

TMS

TMS

TMS

P

P P

P

Li+(DME)

Fe(CO)2(Cp*-η5) E TMS

44 (E = P, As) 42

43

Reaction of 39 with AlCl3 in the presence of Ph3P results in the formation of the phosphine adduct of a methylenediylphosphenium cation 46. A similar product 47 containing the same cation was obtained by treatment of the phosphaalkene 45 with Ph3P. Finally, the phosphaalkene 46 reacts with (Ph3P)2Ni(COD) to give the complex 48 via a phosphine shift from phosphorus to the metal (Scheme 12) .

TMS P TMS

Y

AlCl3, Ph3P

TMS

Y = Cl

TMS

P + AlCl4 PPh3

–

46

39, Y = Cl 45, Y = TfO

Ph3P Y = TfO

TMS P TMS

+

TfO–

PPh3

(Ph3P)2Ni(COD)

TMS

–COD

TMS

47

–

AlCl4

+

P Ni(PPh3)3 48

Scheme 12

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

671

Fischer-type carbene pentacarbonyltungsten complexes, which are functionalized by the bis(TMS)methylenephosphino moiety bonded to oxygen 49 or nitrogen 50, are synthesized by reaction of the O-Li and N-Li precursor carbene complexes with 39 (Equation (10)) . Concerning the last example, it is worth noting that metallaheterobutadiene species of the type 50 easily rearrange into 2H-azaphosphirenes .

TMS

TMS

XLi P

TMS

+

(OC)5W

Cl

Ph

Et2O, –30 °C

Ph P

TMS

W(CO)5

X

ð10Þ

49, X = O

39

50, X = NH

(iv) Miscellaneous Dichlorophosphino ylide TMS(Cl2P)C¼PPh3 loses a chloride ion to Lewis acidic metal chlorides (AlCl3, GaCl3, and SnCl4). In the (E)- and (Z)-isomers so generated, a considerable part of the phosphenium charge is transferred to the phosphonium center leading to a phosphaalkene structure 51 . So far, very little is known about compounds containing a Ge2C¼PY backbone. In view of this, it is interesting to note that in the absence of trapping reagent, the germaphosphaallene Mes2Ge¼C¼P-Mes* gives two types of dimers: the ‘‘classical’’ head to tail dimer 52 and the dimer 53 due to cycloaddition between a Ge¼C and a P¼C double bond. The dimer 53 is the major product .

R

TMS +

P Cl

Ph3P

P R

R P – MCln

51 MCln = AlCl4, GaCl4, SnCl5

6.22.1.2.5

R Ge

Ge R R 52 R = 2,4,6-But3C6H2

R Ge R

R P P R Ge R R 53

R = 2,4,6-But3C6H2

Metallated methylenephosphines, LnM(X)C¼PY

These have been intensively studied in the last few years because of their potential as synthetic blocks in organic chemistry .

(i) Phosphaalkenyl metal species The compounds M(Hal)C¼PY are the phosphorus analogs of alkylidene carbenoids and useful synthons for novel C-functionalized phosphaalkenes (vide supra). Halogen–lithium exchange reactions provide the most general method for the preparation of phosphaalkenyllithium derivatives. Recently new developments in this area have been reported. Treatment of THF or DME solutions of the phosphaalkene Cl2C¼PMes* 3 with excess n-butyllithium afforded cleanly the corresponding carbenoid as DME-solvate ((Z)-54a) or THFsolvate ((Z)-54b). (E)-54 was generated analogously by metallation of (E)-Cl(H)C¼P-Mes* with excess BunLi and identified by 31P NMR spectroscopy. Unlike the (Z)-isomer, (E)-54 was found to be unstable under reaction conditions and decomposed to give Mes*C¼P and Mes*(Li)C¼PBun as main products .

672

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal (solv)n Li

Cl P Mes*

Cl

P Mes*

(solv)n Li

(E )-54 (solv = THF, n = x)

(Z )-54a (solv = DME, n = 2) (Z )-54b (solv = THF, n = x)

The phosphaethenyllithium reagent 54 was transmetallated with MgBr2, ZnCl2, and HgCl2 to furnish the new carbenoids 55. Bis(phosphaalkenyl)–metal species 56 can be made by reacting (Z)-54 with 0.5 equiv. of the metal halide (Scheme 13). The stability order of the newly formed phosphavinylidene carbenoids corresponds to the expected sequence Li < Mg < Zn < Hg. Whereas (Z)-54 decomposes at temperatures above
50  C, the magnesium carbenoids 55a and 56a slowly decompose at 15  C. The zinc carbenoids 55b and 56b are stable at room temperature for at least a few days. The mercury carbenoids 55c and 56c are the most stable one; they can be stored at room temperature in the air . Li Cl

XM

MX2

P Mes*

THF, –110 °C

P Mes*

Cl

(Z )-54

55a–55c MX = MgBr (a), ZnCl (b), HgCl (c)

Mes*

Cl P

0.5 MX2

M THF, –110 °C

P Mes*

Cl 56a–56c

M = Mg (a), Zn (b), Hg (c)

Scheme 13

Bromium–lithium exchange at
90  C between (Z)-Br(TMS)C¼PMes* and BunLi furnished ((E)/(Z))-Li(TMS)C¼PMes* ((E)/(Z) = 1:1). Transmetallation of the latter with MgBr2 or ZnCl2 furnished only the trans-metal isomer of XM(TMS)C¼PMes* (MX = MgBr, ZnCl) . A convenient synthesis of 1-arylthio-2-phosphaethenyllithiums (Z)-57 is based on brominelithium exchange of (Z)-14 with n-butyllithium. During the reaction, the (E)/(Z)-isomerization was observed even at
100  C in THF. Treatment of (Z)-57 with 0.5 equiv. of HgCl2 in THF affords the corresponding organomercury compounds 58. The transmetallation with CuCl2 gives the 1,4-diphospha-1,3-butadiene derivatives 59 as homocoupled products presumably via the corresponding phosphaalkenylcopper species (Scheme 14) .

(ii) Bridging aryl isocyaphide ligands Weber and co-workers reported the synthesis of a diiron complex 60 with a bridging CPR ligand in which the aryl isocyaphide is C-bonded to two metal atoms (Equation (11)). S Me

OC Fe Cp

+ CO

Fe Cp O

Mes*P(TMS)H, DBU –TMS–SMe, –DBU.H+

P

OC Fe Cp

Mes* CO Fe Cp

O 60

ð11Þ

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal ArS P Mes*

Br

BunLi

ArS

THF, –100 °C

Li

(Z )-14

673

Li P Mes*

–100 °C

P Mes*

ArS

(E )-57

(Z )-57

Ar S

0.5 HgCl2 60–79%

P Mes* Hg

Mes* P

S Ar 58

CuCl2

Cu P Mes*

ArS

O2 38–84%

Ar = Ph, 4-MeC6H4

Ar Ar

Mes* P

S S

P Mes* 59

Scheme 14

Further consideration has been given to the semi-bridging isocyaphide platinum complexes 63 . The syntheses of 63 begin with the platinum complexes 61, whose preparation was reported previously . Although no intermediates were observed by 31P NMR spectroscopy during the reaction with Pt(PEt3)4, a possible mechanism for the formation of 63 could involve intermediates 62 resulting from oxidative addition of the C-Hal bond to Pt(PEt3)4. Loss of PEt3 from this intermediate followed by Pt
Pt bond formation would give the final product. Complexes 63 were also prepared by the direct reaction of Cl2C¼PMes* with 2 equiv. of Pt(PEt3)4 in benzene at room temperature but the yield (92%

159 R = c-Hex2N

R1

Bun P R R

160, R1 = Me 161, R1 = Ph2P

Scheme 40

The gallyl-substituted ylide Me2Ga(TMS)C¼P(NR2)2Me is also accessible by reaction of a stable phosphinyl(silyl)carbene with GaMe3 .

6.22.1.5

Tetracoordinate Arsenic, Antimony, and Bismuth Derivatives

In comparison with C,C-diheterosubstituted phosphonium ylides (X1X2C¼PY3), the area of respective arsenic, antimony, and bismuth derivatives is poorly explored . This may have been due to the lack of general methodology for the synthesis of suitable precursors and in part to the low thermal stability of compounds bearing a formal EV¼C double bond (E = As, Sb, Bi). The difference between phosphonium ylides and their heavier analogs is commonly ascribed to the less efficient overlap between the sp2-C orbitals and the larger and more diffuse 4d orbitals of arsenic, stibium, and bismuth. Therefore, contribution of the ‘‘covalent’’ canonical form should become smaller as compared with the corresponding phosphonium ylides. Arsonium, and especially stibonium and bismuthonium ylides, are commonly less stable than their phosphorus counterparts and have a tendency to decompose both in solution and in solid state unless there is electronic stabilization. A significant increase in stability of the ylides X1X2C¼EY3, is observed, however, if electron withdrawing groups (X) such as carbonyl or sulfonyl are conjugated with the ylidic carbon atom . The methods available for the synthesis of arsonium, stibonium, and bismuthonium ylides are nearly all analogous to methods used for the corresponding phosphonium ylides.

6.22.1.5.1

C,C-Diheterosubstituted arsonium ylides, X2C¼AsY3

Bis(sulfonyl)methylenetriphenylarsoranes, (RO2S)2C¼PPh3, remain only one type of well-characterized and studied C,C-diheteroatom-substituted arsonium ylides. No information about synthesis of other C,C-diheterosubstituted species is available since the publication of chapter 6.22.1.5.1 in COFGT (1995) .

6.22.1.5.2

Stibonium and bismuthonium ylides bearing heterosubstituents, X2C¼EY3 (E = Sb or Bi)

Yagupolskii and co-workers have described synthesis of a new bis(trifluoromethylsulfonyl)substituted stibonium ylide . Treating Br2C(SO2CF3)2 with 3 equiv. of tributylstibine results in the formation of stable stibonium ylide 162 (Equation (24)). The same group has also shown that treatment of sodium derivatives of the corresponding bis(sulfonyl)methanes with Ph3BiCl2 gives rise to the bismuthonium ylides 163 (Equation (25)). From the NMR spectra, zwitterionic canonical structures containing Bi+–C
or Bi+–C¼S–O
units may be assumed .

688

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal CF3O2S CF3O2S

CF3O2S

Br + Br

3Bu3n Sb

50%

+ – X SbBu3n

CF3O2S

ð24Þ

162 RfO2S RfO2S

Na

RfO2S

Br

+

Ph3BiCl2

– + X BiPh3

>90%

ð25Þ

RfO2S 163 Rf = F3C, n-C4F9, OCH2CF2CF2H

The synthesis, characterization, and solid-state structure are described for a reversed ylide 164, derived from 1,3-dimesityl-4,5-dichloroimidazol-2-ylidene and tris(trifluoromethyl)antimony (Equation (26)) . According to X-ray data, the ylide 164 retains reactantlike geometries for both the component fragments and is thus predisposed to facile cleavage of the carbene–antimony bond. Variable temperature solution NMR spectroscopic studies suggest that the carbene fragment readily dissociates from antimony center at temperatures as low as
95  C. Cl

Mes N

Cl

N Mes

Cl +

(F3C)3Sb 92%

Cl

Mes N – + X Sb(CF3)3 N Mes

ð26Þ

164

6.22.2

FUNCTIONS CONTAINING A DOUBLY BONDED METALLOID

6.22.2.1

Tricoordinate Silicon and Germanium Derivatives

Progress over the past decade in the chemistry of p–p systems involving carbon and the heavier group 14 elements (Si, Ge) has been reviewed . The most readily available reaction pathways used to produce C,C-diheterosubstituted sila- and germaethenes are: (i) 1,2-elimination of a salt (LiY) from -lithiated silanes or germanes R2E(Y)–C(Li)R2 carrying a good leaving group (Y) on the element atom, (ii) 1,2-(Si
C) silyl carbene–silaethene rearrangement, and (iii) coupling between a silylene or germanium(II) derivative and a nucleophilic carbene.

6.22.2.1.1

Diheterosubstituted silaethenes, X2C¼SiY2

Full details have appeared of studies of the formation, detection, and stabilization of the shortlived silaethene 167 . This compound is formed by reaction of trisilylmethanes 165 with alkali metal organyls or silyls via intermediates 166 and, in the absence of trapping agents, reacts with 166 to give the compounds 168, which in turn eliminate MX under formation of the 1,3-disilacyclobutane 169. In the presence of an excess of organyl or silyl azides, which act as very active trapping reagents for the silaethene, the [3+2]cycloadducts 170 are formed (Scheme 41). Direct detection of the silaethene 167 has been accomplished by laser-flash photolysis of Me3SiMe2SiC(N2)SiMe3 . Bromotrisilylmethanes 171–173 have been used as sources of the corresponding isomeric silaethenes with six Me and two Ph substituents. Phenyllithium converts the above compounds by Br/Li-exchange to lithium organyls, which in ether solution are in equilibrium with unsaturated silicon derivatives. The intermediacy of the silaethenes has been established by their trapping with 2,3-dimethylbutadiene .

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal Me

TMS TMS Br

RM

Si Me –RBr

X

Me

TMS TMS M

Si Me X

166

165

–MX TMS TMS M

689

Me TMS Me

166

+MX Me

TMS Si

Si

Si Me TMS X Me

TMS

168

Me 167

R1N3 TMS Me2Si TMS SiMe2 TMS TMS

TMS

TMS SiMe2 N N R1 N 169

170

RM = BunLi, PhLi, (TMS)2CHLi, Bu3t SiNa; X = F, Br, PhO

Scheme 41

R R1 Br

Ph Si Me Br 171

R R2 Br

Me Si Me Br 172

Me R1 Si Me R1 Br Br 173

R = TMS, R1 = PhMe2Si, R2 = Ph2MeSi

Dehalogenation of the sterically overloaded trisilylmethanes R*(TMS)BrC–Si(X)Me2 has been exploited for the synthesis of silaethene R*(TMS)C¼SiMe2 (R* = But3Si). Reaction of R*(TMS)BrC–Si(X)Me2 (X = F, TfO) with PhLi leads to R*(TMS)LiC–Si(Ph)Me2, while R*(TMS)BrC–Si(F)Me2 reacts with But3SiNa to give R*(TMS)NaC–Si(F)Me2. The latter compound transforms in THF in the presence of Me3SiCl into the corresponding silaethene, which may be trapped by reactants like MeOH, Me2CO, or 2,3-dimethylbutadiene. It follows from this study that the metastability of compounds (ButnMe3
n Si) (TMS)C¼SiMe2 with an increasing number of But groups pass through a maximum for n = 2 . Using a new synthetic pathway, Oehme and co-workers recently succeeded in preparing a variety of new C,C-disilyl-substituted silaethenes. They observed that dichloromethyltris(trimethylsilyl)silane reacted with an excess of organolithium reagents RLi (R = Me, Bun, Ph) under substitution of the two chlorine atoms and a complete reorganization of the whole substitution pattern of the molecule to produce silanes of the type (TMS)2CH–Si(TMS)R2 . As shown in Scheme 42, in this process the transient silaethenes 174 and 175 occur as intermediates, which are trapped by the organolithium reagent present in the reaction mixture, and the reaction affords 176 as the end product after aqueous workup. However, if, for the reaction with Cl2CHSi(TMS)3, an organolithium reagent is chosen with a group R, which, when introduced at the silicon atom, provides sufficient stabilization of a silaethene system through an intramolecular donor–acceptor interaction, it possible to halt the reaction at this stage and to isolate a silaethene. This was achieved, for example, in the reactions of Cl2CHSi(TMS)3 with suitably functionalized organolithium compounds in the molar ratio 1:2,

690

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

which led to the isolation of intramolecularly donor-stabilized silaethenes 177–179 . By the use of sterically congested organolithium derivatives, the nucleophilic addition of RLi to the C¼Si bond can also be prevented and kinetically stabilized silaethenes obtained. Thus, silaethene 180 was synthesized by the reaction of Cl2CHSi(TMS)2Ph with 2,4,6-triisopropylphenyllithium. Similarly, silaethenes 181 and 182 were prepared from Cl2CHSi(TMS)3 and 2,4,6-triisopropylphenyllithium or 2-t-butyl-4,5,6-trimethylphenyllithium (Scheme 43) .

Cl

TMS

Cl

–RH

TMS

TMS Si TMS

Cl Li Cl

RLi

Si TMS

TMS Si TMS

–LiCl

Cl

TMS

TMS

TMS

TMS Si

Cl

TMS 174

RLi

Cl Li TMS

R Si TMS TMS

for RLi = MeLi, BuLi, PhLi –LiCl

for RLi = Li–D –LiCl

TMS

TMS TMS

D

TMS

Si

Si

R

TMS

175

TMS

i. RLi ii. H2O TMS

TMS

Si R TMS

R 176

Scheme 42

Me2N TMS

Me2N TMS Si

TMS

Si TMS

177

Me2N TMS

TMS

TMS 178

NMe2 Si

TMS

TMS 179

Ottosson and co-workers have used Brook’s procedure to generate transient silaethenes R2N(TMS-O)C¼Si(TMS)2 (R = Me, Ph). Formation of the latter through photolysis of the compound Me2NC(O)Si(TMS)3 was attempted before and found to be unsuccessful since no reaction occurred upon long irradiation . In a modification of this

691

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

method, the silaethenes have been prepared by thermolysis of the silylamides R2NC(O)– Si(TMS)3. The short-lived silaethenes are trapped with 2,3-dimethylbutadiene to quantitatively yield only one of the possible diastereomers of the cyclic allylsilanes. Ab initio calculations reveal that the silaethene Me2N(TMS-O)C¼Si(TMS)2 is characterized by reversed C+–Si
bond polarization and features a carbon–silicon single bond and a pyramidal silicon atom.

Cl

TMS

TMS

TMS

R2Li

Si

Si TMS Cl

R1

–R2Cl, –LiCl

Cl

R2

TMS Li Cl

R2Li

R1

TMS

Si TMS R1

R2

TMS –LiCl

Si TMS

R1

TMS Si

TMS

Si TMS

1

R 180, R1 = Ph

TMS 182

181, R1 = TMS

Scheme 43

Related carbene–silylene adduct 183 in which the C
Si bond is best formulated as being electrostatic in nature, with the carbene moiety as electron donor and the Si(NN) fragment as acceptor, has been prepared according to Scheme 44. The compound 183 is monomeric, with the three-coordinate C and Si atoms in an almost planar (C) or pyramidal (Si) environment .

R NH NH R

Cl2CS

R N S N R

C8K

R N Si N R

R N N R

Pentane, –25 °C 83%

R R N – N + Si N N R R 183

Scheme 44

6.22.2.1.2

C,C-Diheterosubstituted germaethenes, X2C¼GeY2

The C¼Ge bond is of low intrinsic thermodynamic stability, so that stable germaethene derivatives all contain sterically bulky substituents at both germanium and carbon . Uncomplicated germaethenes exists only as transient species. The methods available for their synthesis are nearly all analogous to methods used for the corresponding silaethenes . The most established process for the generation of transient C,C-diheterosubstituted germaethenes is based on the formation of the C¼Ge bond by the salt elimination method. For example, germaethene (TMS)2C¼GeMe2 is formed as a short-lived intermediate by reaction of (TMS)2BrC–GeMe2X with RLi via (TMS)2LiC–GeMe2X (X = electronegative substituent, R = organyl) . Interestingly, thermolysis of 184 at 100  C in the presence of propene, butadiene, 2,3-dimethylbutadiene or isobutene leads to ene reaction product and/or [4+2]-cycloadducts of the germaethene 186. The formation of these trapping products proves the intermediate existence of a compound with Ge¼C bond and indicates that the equilibrium between 185 and 186 lies at the side of germaethene (Scheme 45) .

692

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal Me3Ge Me3Ge Li

But Si But F

100 °C

Me3Ge

But

–LiF

Me3Ge

But

184

Me

185

Me

GeMe3

Me Ge

80%

SiMeBut2

GeMe3 Me

Ge Me

SiMeBu2t

77%

Me GeMe3 Ge SiMeBu2t

186

Scheme 45

Recently, the [4+2]-cycloadduct of (TMS)2C¼GeMe2 and anthracene has been proposed as a ‘‘store’’ for the germaethene . Adduct 188 can be prepared by reaction of an excess of anthracene in benzene with germaethene precursor 187. Above 100  C it decomposes reversibly via thermal cycloreversion into (TMS)2C¼GeMe2 and comparatively unreactive anthracene. The half-life of the anthracene adduct in the presence of 2,3-dimethylbutadiene (DMB) in t-butylbenzene on thermolysis at 130  C is found to be 12 h. In the absence of DMB, thermolysis leads to the dimer of the germaethene (Scheme 46). TMS TMS Li

Me Ge Me OPh

100 °C

TMS

Me Ge

–PhOLi

TMS

Me

187

TMS

TMS GeMe2

188 t-BuC6H5 130 °C Me TMS Me Ge TMS

TMS Me2Ge TMS GeMe2 TMS TMS

Scheme 46

Among the stable C,C-diheterosubstituted germaethenes the only well-characterized and studied compounds are adducts obtained from the germylenes and the free carbenes. New examples are the germaethenes 189 and 190 prepared by reactions between the appropriate germanium(II) compounds and nucleophilic carbenes . Related carbene–germylene complex 191, in which the ring represents a diborylcarbene system, is also readily available from its factors, the kinetically stable diarylgermylene and Berndt’s carbene . It should be made clear that the structures of 189 and 190 are best described as a Lewis base–Lewis acid adducts in which the newly formed C
Ge bond is not a true double bond but rather highly polarized C+
Ge
bond. In contrast, the X-ray structure analysis as well as NMR data of cryptodiborylcarbene adducts 191 suggest some significance for the ylide resonance formula of type C

Ge+, expected from the interaction between an electrophilic carbene and a nucleophilic germylene .

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal Mes N – + Ge I N I Mes

R R N – N + Ge N N RR

189

But B

TMS TMS

190, R = ButCH2

693

B But

Ge RR

191, R = 2-But-4,5,6-Me3C6H

Phosphino(silyl)carbene 192 reacts with germylenes affording the C-germylphosphaalkenes 194 (Scheme 47). It is reasonable to postulate the primary formation of the germaethenes 193, which would undergo a subsequent 1,3-shift of Me2N group from phosphorus to germanium atom to produce compounds 194. The instability of 194 is not surprising whatever the polarity of the C¼Ge bond, since the phosphorus center is not efficient enough to stabilize an adjacent positive charge and destabilizes a negative charge . Tmp

Tmp Me2N P

Me2N P +

GeR2

TMS

THF, rt

192

TMS

R Ge R

Tmp P 47–68%

R Ge NMe2 R

TMS

194

193

R = (TMS)2N or Mes*NH, Tmp = 2,2,6,6-tetramethylpiperidino, Mes* = 2,4,6-But3C6H2

Scheme 47

Okazaki and co-workers prepared the first stable germaketenedithioacetal 197 by treatment of overcrowded diarylgermene 195 with carbon disulfide. The formation of 197 can be reasonably interpreted in terms of the intermediacy of thiagermiranethione 196, as shown in Scheme 48. Exclusive formation of 197 without any 1:1 addition product, even in the presence of an excess amount of carbon disulfide, implies a much higher reactivity of the thiocarbonyl unit of 196 toward germylene 195 than that of carbon disulfide . Tbt Tbt Ge Tip

CS2 THF, rt

Tbt

Tbt

– +

Ge

Ge S C S

S

Tip

Tip

Tip

Ge

195 S

S + –

S Ge

Tbt Tip

196

195

46%

S

Tbt Ge Tip

Tbt Ge S Tip

197 Tbt = 2,4,6-[(TMS)2CH]3C6H2, Tip = 2,4,6-Pr3i C6H2

Scheme 48

6.22.2.2

Functions Incorporating a Doubly Bonded Boron

Among organoboron compounds many C,C-disilyl-substituted doubly bonded molecules have now been synthesized, such as methyleneboranes 198, 2-borataallenes 199, and boriranylideneboranes 200. Stable methyleneboranes are obtained only when the C¼B double bond is sterically shielded by large substituents. In addition, electronic stabilization is necessary either through formally nonbonding electron pairs on the atoms directly adjacent to the dicoordinated boron atom or through electropositive substituents at the position  to the dicoordinated boron atom.

694

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

Thus in amino-substituted methyleneboranes 198 (Y = R2N) or 2-borataallenes 199, the electron deficiency at the dicoordinated boron atom is relieved through – delocalization of the formally nonbonding electron pairs on the neighboring atom. In nonclassical methyleneboranes 200, the electron-deficient center at the dicoordinated boron atom forms nonclassical three-center, twoelectron (3c–2e) bonds with neighboring
bonds. X X

X B Y

X

R

–

M+

B X

198

R B B R

X

R 199

200

There are a number of specialized methods for the formation of X2C¼B functions which, however, do not seem to have general applicability. For further details a comprehensive review on this subject should be consulted .

6.22.2.2.1

Methyleneboranes, X2C¼B-Y

Various synthetic pathways for the formation of X2C¼BY species are outlined in Scheme 49 . The simplest route involves a 1,2-elimination reaction at organoboranes having functional substituents X at carbon and Z at boron atom which combine to a thermodynamically favored leaving molecule XZ, e.g., Me3SiF. This is currently the method of choice in the synthesis of C,C-disilyl-substituted methyleneboranes of the general formula (TMS)2C¼BY . Methods involving either the cleavage of B
C single bonds in (borylmethylene)– boranes or reactions of borataalkynes with electrophiles have also proved sufficiently effective . Finally, the thermal cycloreversion of 1,3-diboretanes and 1,2-dihydroboretes is of considerable potential for the generation of methyleneboranes .

X X

Y

B

–

B X

B

TMS

Li+ C B

Z TMS

Cycloreversion (–TMS

Elimination (–XZ)

X B Y

X

TMS)

Reactions with electrophiles (+E+)

Cleavage of C–B bond

B Cl

Reductive elimination

Reductive cleavage

B B

–

–

B C B

2Li+

B Cl

Scheme 49

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

695

The organic chemistry of boriranylideneboranes 200, obtained by Berndt and co-workers in the early 1980s through reductive elimination and rearrangement of the diborylalkenes has been extensively studied and is characterized by cleavage of bonds in the threemembered ring and migration of substituents . These species seem to be valuable starting materials for the synthesis of new type of heterosubstituted methyleneboranes. Thus, the boriranylideneboranes 200a and 200b add B2Cl4 under cleavage of the Si2C
B bond to yield the (borylmethylene)boranes 201 in which three boron atoms are bonded to a methylene carbon (Equation (27)) . Reaction of the t-butyl derivative 200c with [Co(Cp)(C2H4)2] provides the metalacycle 202 featuring the metal-substituted C¼B double bond (Equation 28) . TMS

R

R B

B2Cl4 B R

TMS

Hexane, –85 °C 33–50%

200a, 200b

Cl

B B

Cl

B

TMS BCl2 TMS

R

ð27Þ

201 R = Dur (a), Mes (b)

TMS

But B

TMS

B But

[Co(Cp)(C2H4)2]

TMS

Hexane, reflux, 0.5 h

TMS

Co B B But

But

ð28Þ

200c 202

6.22.2.2.2

2-Borataallenes, [X2C¼B¼CY2]


Among possible synthetic strategies for 2-borataallenes, thermally induced isomerization of C-borylboriranide 203 prepared from 200a by reaction with phenyllithium or 2-boryl-1,3-diboretanides 205 accessible from the reaction of 204 with t-butyllithium play an important role. In the last case, authors suggest the 1-bora-3-boratabutadiene as an intermediate, whose transformation into 2-borataallene requires a 1,3-migration of an aryl group from the tri- to the dicoordinated boron atom. Reductive dimerization of the methyleneborane 198a has also been used in the synthesis of borataallenes (Scheme 50) . The 1-boryl-2-borataallenes react with electrophiles to form the (borylmethylene)boranes .

6.22.3

FUNCTIONS INCORPORATING A DOUBLY BONDED METAL

For the purpose of this survey, the above functions will be defined as the species of the formula X1X2C¼MLn (X1, X2 = heteroatom substituents), which formally contain a double bond between carbon and metal. Until 1990s, apart from the well-studied transition metal–dihalocarbene complexes, there was comparatively little information on compounds involving C¼M bonding between three-coordinate diheterosubstituted carbon and metal . The situation has changed recently. A breakthrough was the isolation of the first free N-heterocyclic carbene (NHC) by Arduengo and co-workers . Since then NHCs and related acyclic diaminocarbenes have become accessible as ‘‘bottle-able compounds’’ and their inorganic and organometallic chemistry has gained enormously in versality and depth . Numerous new varieties of diheterosubstituted carbene complexes were reported within a short period of time. The reviews by Herrmann , Arduengo , Bourissou and co-workers , and Enders and Gielen provide a valuable survey of the literature up to 2002. In comparison with transition metal–carbene complexes, the area of respective molecule with carbon–Main Group metal double bond remains rather poorly explored .

696

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal Dur B

TMS

TMS B Dur

PhLi

Ph

TMS –

TMS

B

TMS

∆

B

TMS

B Dur

Dur

Dur

Li+

200a

Ph B Dur Li+

203 1,2-Dur shift

TMS

–

B TMS

TMS B TMS

TMS

Li

Li+

TMS

–

0.5

B Dur Dur

TMS

Ph B Dur Li+

Dur

Dur –

B

–

TMS

TMS

2Li+

B TMS

198a

Ar B

TMS TMS

B Ar

B Ar

ButLi

TMS TMS

Ar But B – B B Ar Ar Li+

∆

TMS TMS

Ar B–

But

TMS

–

Ar B But

B

B Ar B Ar Li+

TMS Li+

B Ar Ar

Ar = Dur, Mes 205

204

Scheme 50

6.22.3.1 6.22.3.1.1

Transition Metal–Carbene Complexes N-Heterocyclic carbene complexes

The use of N-heterocyclic carbenes I–IV and related acyclic diaminocarbenes is a recent development in the synthesis of transition metal–carbene complexes (Figure 2) . Experimental and theoretical studies have established that NHCs bind to the transition metal by
-donation; back-donation from the metal is minimal, thus the electronic properties of diheterosubstituted singlet carbenes are comparable to trialkylphosphines. Typical procedures for the synthesis of NHC–transition metal complexes are: (i) free carbene route (deprotonation of the corresponding azolium salts with bases prior to metallation; (ii) direct metallation of the azolium salts with a basic metal precursor such as Pd(OAc)2 or [Ir(COD)(OEt)]2; (iii) reaction of the corresponding electron-rich alkenes (enetetramines) with mononuclear or bridged dinuclear organometallic compounds; (iv) metal exchange starting from silver carbenes (transmetallation); and (v) oxidative addition of a low-valent metal to a 2-chloro-1,3-disubstituted imidazolinium salt. R N

R N

R N

R

N R

N N R

I

II

( )n N

III

Figure 2 N-Heterocyclic carbenes.

R N S

IV

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

697

A new approach to the preparation of NHC–transition metal complexes was recently reported by Cloke and co-workers . It concerns the possibility of obtaining group 10 homoleptic carbene complexes via the co–condensation of nickel, palladium, or platinum vapor with 1,3-di-t-butylimidazol-2-ylidene. This route provides a straightforward synthesis of the stable, two-coordinate metal–carbene complexes 206–208, one compound of which 207, has been inaccessible to date by solution technique (Equation (29)). But

But But

N

N

Cocondense

2

+

M(at)

N

N M

–196 °C

N

N But But

But

ð29Þ

206, M = Ni 207, M = Pd 208, M = Pt

Another interesting example of the formation of transition metal–carbene complex from free NHC is the preparation of vanadium(V)–carbene adduct 209 in which the transition metal is in a high oxidation state (Equation (30)). In this case, complexation of an N-heterocyclic carbene to vanadium(V) results in an electrophilic singlet Ccarbene, which is typical of Fischer type systems, but is unusually supported by a high-oxidation-state metal center. Both solid samples and dichloromethane solutions of 209 are stable in air and showed no decomposition on standing for over two months . Mes

Mes

N

N +

N Mes

Cl3VO

Toluene, rt 76%

V(O)Cl3 N

ð30Þ

Mes 209

Erker and co-workers used three different stable imidazole-derived carbene ligands to prepare a series of trans-[(imidazolyl-2-ylidene)2MCl4 complexes of zirconium and hafnium . Scheme 51 illustrates synthetic approaches to these species. Deprotonation of 1,3-diisopropylimidazolium chloride 210 with NaH–KOBut gave 1,3-diisopropylimidazol-2-ylidene 213 in 95% yield. Treatment of N-methylimidazole with 2-bromobutane yielded the imidazolium salt 211 which was converted to the stable carbene 214 by treatment with KH–KOBut. Finally, the imidazolium salt 212, prepared by N-alkylation of N-methylimidazole with bromomethyl-2,4,6trimethylbenzene, was converted to the unsymmetrically substituted Arduengo carbene 215 by treatment with NaH in THF. Reaction of the carbenes 213–215 with MCl4(THF)2 (M = Zr, Hf) affords the corresponding carbene–group 4 Metal halide complexes 216–219 as stable solids. The first carbene-linked cyclophane 221 was prepared by Youngs and co-workers from the bis(imidazolium) salt 220, which results from a straightforward alkylation reaction of 2,6-bis(imidazolemethyl)pyridine. Silver oxide was used to deprotonate 220 and, at the same time, to introduce the metal center (Scheme 52) . As a further development of the free carbene route the synthesis of N-borane-protected NHC complexes has been achieved as shown in Scheme 53. 1,10 -Bis(3-borane-4,5-dimethylimidazolyl)methane 222 was deprotonated to give a dianionic dicarbene compound 223. Its reaction with Cp2MCl2 (M = Ti, Zr) allowed the formation of the corresponding titanocene and zirconocene complexes 224 and 225 in 75–80% yields . Metal acetates allow the synthesis of NHC complexes without isolation of free carbenes. This procedure combines the advantages of readily available starting materials with the in situ deprotonation of the azolium salts and avoids free carbenes or expensive organometallic precursors. For example, since the acidic methylene protons in bisimidazolium salts 226 are also attacked under common deprotonation conditions, a pathway via free biscarbenes leads to a complex mixture of products. However, palladium(II) acetate in wet DMSO deprotonates 226 to give bridged palladium–biscarbene complexes 227 in 85–90% yields . The bisimidazolium salts 226 also undergo a selective deprotonation with sodium acetate/platinum(II) halide, and this has been used in a one-pot synthesis of novel platinum(II) biscarbene complexes 228 (Scheme 54) .

698

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal Cl–

N+

NaH/KOBut

N

MCl4(THF)2

N

THF, 95%

N

91–99%

N

H

MCl4

N

210

2

216, M = Zr

213

217, M = Hf Br–

N+

NaH/KOBut

N

ZrCl4(THF)2

N

THF, 65%

N

89%

N

H N

211

ZrCl4 2

218

214 Br–

N+

NaH

N

ZrCl4(THF)2

N

THF, 86%

N

94%

N

H N

ZrCl4

215

212

2

219

Scheme 51

2+ 2PF6–

N N

N H H

N

N +

Br

Br

N i, ii

N + N

N

H H N

N N + N

Ag2O DMSO 55 °C

2PF6–

N

N

N Ag

N Ag

N

N

N N

N 220 221

i. CH2Cl2, rt; ii. NH4PF6

Scheme 52

Interestingly, the pK’s of the bisimidazolium salts 226 should make one think that NEt3 is not strong enough to deprotonate the azolium center. Nevertheless the addition of an excess of the base (20:1), together with the rapid coordination of the carbene to metal, displays the equilibrium of deprotonation to the formation of the desired products. Thus the synthesis of complexes 229 and 230 includes the deprotonation of the bisimidazolium precursor with NEt3 in the presence of [RhCl(COD)2]. When the reaction is carried out in the presence of air, 229 is the major product obtained. Under inert conditions with degassed acetonitrile, complex 230 is mainly formed . A similar approach has been applied to the preparation of dirodium(I) bisimidazolium carbene complex 231 and new ruthenium(II) CNC-pincer bis(carbene)complexes 232 and 233 (Scheme 55) .

699

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

N

2BH3.THF

N

THF, –78 °C 97%

N

N

N

N N BH3

N H3B 222

2– 2BuLi

N

THF, –78 °C

Cp2MCl2

N 2Li+

N BH3

N H3B

N

THF, –78 °C

N

N N M H3B Cp Cp BH3

223

224, M = Ti (75%) 225, M = Zr (80%)

Scheme 53

N 2

CH2X2

+

+

N

N

N

DMSO, rt

N R

N R

N R

Pd(OAc)2 or 2X– PtX , 2NaOAc 2

N

N N M X R R X

226

227, M = Pd 228, M = Pt

R = Me, Bun; X = Br, I

Scheme 54 [RhCl(COD)]2

N + N

N

NEt3 + KI + KPF6

+ 2I–

N

Rh

CH3CN

N

N

+ N

I

I

N

N or

Rh

N

N

N I Rh I MeCN NCMe 230

229

Scheme 55

Bun N

N

N Rh

N Br

Br

N Bun

N

Br N Ru N N Br CO Bun Bun N

Rh

232

231

2PF6–

C C N

Ru C C

N N 233

C

N N=

N Bun

N

N N Bun

+ PF6–

700

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

A further exploitation of the azolium route now covers metallocenes, such as 234. This synthesis is successful for both nickelocene and chromocene (Equation (31)) . Mes N

Cl–

Mes N

+

THF

M

+

Cl

–C5H6

N Mes

M

N

ð31Þ

Mes 234 M = Ni (70%), Cr (67%)

A recent paper has described an efficient entry into palladium complexes bearing NHC ligands on the basis of the oxidative addition Pd(PPh3)4 to the easily accessible 2-chloro-1,3-disubstituted imidazolium salt 235 . This novel method promises a broad substrate scope and allows for substantial structural variations since the required 2-chloro-1,3-disubstituted imidazolium salts can be easily prepared from cyclic ureas or thioureas on treatment with, for instance, oxalyl chloride. Examples are depicted in Schemes 56 and 57. Interaction of the imidazolium salts 235 (X = PF6, BF4) with an equimolar amount of Pd(PPh3)4 in refluxing dichloromethane leads to the formation of cis-236 as the primary products, which isomerize with time to the more stable trans-236. Although the reactivity of chloride 235 (X = Cl) follows the same trend, giving rise to the expected cationic complex trans-236 in 87% yield, the equilibrium between the cationic and the neutral Pd–NHC complexes leads to small amounts of complex 237 in addition to 236. This propensity is more pronounced in case of the enantiomerically pure NHC complex 239, which is obtained as the only product on treatment of the chiral imidazolium salt 238 with Pd(PPh3)4 under similar conditions.

+ X–

N Cl N

Pd(PPh3)4

N

–2PPh3

N

Cl Pd PPh3 PPh3

+ X–

235 cis-236

N Ph3P

+ N

Cl Pd Cl PPh3

N X = Cl

237

N

PPh3 Pd Cl PPh3

+ X–

trans-236

X = PF6, BF4, Cl

Scheme 56

Complexes of NHC can also be generated starting from aminals. In particular, the successive treatment of [PdCl2(PEt3)2] with the aminal 240 leads to the formation of trans-mono- and transbis(carbene) complexes 241 and 242 containing the 1,3-diallylimidazolidin-2-ylidene ligand. If, in addition, [Pd2Cl4(PEt3)2] is employed, the cis-complexes 243 and 244 are obtained in high yields as the only organometallic products (Scheme 58) . Special NHC-transfer reagents are the silver(I) complexes . They are formed in a simple way by treatment of imidazolium salts with Ag2O and transfer their NHC ligands to other metals, for example, Pd, Pt, or Rh . This technique overcomes the difficulties arising from the use of strong base to yield free heterocyclic carbenes and seems to be particularly effective in the case of functionalized NHCs. For example, Matsumoto and co-workers have demonstrated that the imidazolium chloride 245 reacts with an

701

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

Ag2O suspension in dichloromethane at a ratio of 1:1 to afford 246. Attempt to prepare the free carbene by deprotonation of the imidazolium salt 245 with either KOBut or KH was not successful probably due to the high acidity of the methylene protons linking phenyl and imidazole rings (Scheme 59) . The silver-NHC complex 247 was prepared in a similar manner. It smoothly reacts with [PdCl2(COD)] to yield the corresponding palladium–carbene complex 248 .

[C(O)Cl]2

Cl2C=S 64%

NH HN

N

82%

N S

+ Pd(PPh3)4

Cl– N

–3PPh3

N

N

85%

Cl

N

Ph3P Pd Cl Cl

238 239

Scheme 57

R N NMe2

R N

PdCl2(PEt3)2 –PEt3, –Me2NH

N H R

N R

240

Cl Pd PPh3 Cl

R N

240 –PEt3, –Me2NH

N R

trans-241

R N

[PdCl2(PEt3)]2 –Me2NH

N R

PPh3 Pd Cl Cl

Cl Pd Cl

R N N R

trans-242

R RN N

240 –PEt3, –Me2NH

N R

cis-243

N R Pd Cl Cl

cis-244

R = CH2=CH-CH2

Scheme 58

2Cl– 2

N

N Me

+

Me N

60 °C, 2 h Cl

Cl

N

+

+

91% 245

Ag2O CH2Cl2, rt 95%

Me N

N

N

N Me Ag

Ag

Cl

Cl 246

Scheme 59

N

N Me

702

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal N N

N

N

N

O

O Ag Br

Cl Pd Cl

247

N

248

An entirely different approach for the generation of the metal–NHC complexes is based on the template-controlled formation of NH,O- and NH,NH-stabilized cyclic carbene ligands . An example is outlined in Scheme 60. The 2,3-dihydro-1H-benzimidazol-2ylidene complexes 252 (M = Cr, W) have been produced by template-controlled generation of a carbene ligand from 2-azidophenyl isocyanide and [M(CO)5(THF)]. The polar Ph3P¼N function in complexes 249 can be hydrolyzed with H2O/HBr to afford the unstable 2-aminophenyl isocyanide species 250, which spontaneously cyclize by intramolecular nucleophilic attack of the primary amine at the isocyanide carbon to yield the complexes 251. Double deprotonation of the cyclic NH,NHcarbene ligand in 251 with KOBut and reaction with 2 equiv. of allyl bromide affords the N,N0 dialkylated benzannulated N-heterocyclic carbene complexes 252 .

M(CO)5(THF) N3 N C

THF, rt 63–65%

N3 N C OC M CO OC CO CO

PPh3 THF, rt 75–80%

N PPh3 N C OC M CO OC CO CO 249

HBr/H2O

i. KOBut ii. C3H5Br N

N

OC M CO OC CO CO 252

65%

H N

N

H OC M CO OC CO CO

78–85%

251

NH2 N C OC M CO OC CO CO 250

M = Cr, W

Scheme 60

6.22.3.1.2

Silicon-substituted carbene complexes, R3Si(X)C¼MLn

The silyl(ethoxy)carbene complexes XPh2Si(EtO)C¼W(CO)5 253 and 256 were prepared by the Fischer route starting from W(CO)6 and LiSiPh2X followed by alkylation of the formed anionic acyl complex with [Et3O]BF4. For the synthesis of 256, an excess of [Et3O]BF4 has to be avoided, because otherwise the amino group is cleaved. Reaction of 253 with Me2NH and of 256 with MeNH2 resulted in the formation of the corresponding silyl(amino)carbene complexes 254 and 257 in high yields. When ether solutions of 254 or 257 were irradiated with UV light, CO was

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

703

evolved, and the thermally stable tetracarbonyl complexes 255 and 258 were obtained (Scheme 61). The spectroscopic data clearly showed that the olefinic group in 255 and the amino group in 258 are coordinated to the metal center .

i. LiSiPh2(CMe=CHMe)

EtO

Me2N W(CO)5

ii. [Et3O]BF4 Ph2Si

W(CO)6

Me2NH Et2O, rt 71%

59%

W(CO)5 Ph2Si

254

253 Me2N hν

W(CO)5 Ph2Si

Et2O, –20 °C 93%

255

i. LiSiPh2NEt2 ii. [Et3O]BF4

EtO W(CO)5

W(CO)6 Ph2Si

60%

NEt2 256

hν Et2O, –20 °C 62%

MeNH2

H Me N

Et2O, rt

Ph2Si

95%

W(CO)5 NEt2 257

H Me N W(CO)5 Ph2Si NEt2 258

Scheme 61

Upon photolysis of the carbene complexes R12RSi(R2N)C¼M(CO)5 (M=Cr, Mo, W; or Ph3Si) the stable 16-electron carbene complexes R12RSi(R2N)C¼M(CO)4 are obtained. These species are stabilized by intramolecular interaction of one of the silicon substituents with the metal atom. Thus in Mes2SiH(Me2N)C¼W(CO)4 the Si–H group interacts with the tungsten atom. In the Ph3Si derivative, the W–Cphenyl distances indicate that the ipso carbon atom is mainly involved in the interaction with the metal atom. Despite the agostic interaction in the silylcarbene complexes, the coordination site is still accessible. Thus, the reaction of R12RSi(R2N)C¼M(CO)4 with CO, phosphines, phosphites, or isonitriles quantitatively yielded 18-electron carbene complexes cis-R12RSi(Me2N)C¼W(CO)4L (L=CO, RNC, R3P, (RO)3P) . Formation of the silyl-substituted alkylidene tantalum and tungsten complexes from reactions of alkylidene complexes with silanes have been reviewed . Scheme 62 illustrates this synthetic methodology. Addition of the silanes H2SiRPh to the alkylidene complex 259 leads quantitatively to the disilyl-substituted alkylidene complexes 260. The reaction occurred exclusively with the alkylidene (¼CH–TMS) ligand, and the resulting complexes were found to be unreactive toward excess silane. More interestingly, addition of H2SiRPh to 261 led to the evolution of H2 and the formation of 1,10 -metalla-3-silacyclobutadiene complexes 262. The reaction of 261 with disilylmethane (H2PhSi)2CH2 also generates H2 and a metalladisilacyclohexadiene 263 . Novel products, unavailable by other routes, can thus be prepared. R12RSi¼Mes2HSi

704

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

TMS TMS

PMe3 Ta TMS TMS

H2SiRPh

TMS

TMS Ta

–H2, –PMe3

TMS

RPhHSi

TMS

Hexane, rt 260

259

H2SiRPh –2H2 Pentane, rt 44–78%

Ph R

TMS PMe3 Ta PMe3 TMS TMS 262

TMS TMS

PMe3 Ta PMe3TMS 261

PhH2Si

SiH2Ph

–2H2 Pentane, rt 10%

Ph TMS PMe3 H Si Ta PMe3 H Si TMS Ph TMS 263

R = Me, Ph

Scheme 62

6.22.3.2

Functions with a Formal Tin–Carbon and Lead–Carbon Double Bond

The synthesis and properties of low-coordinated compounds of tin and lead are collected in the recent review by Weidenbruch . Stannaethene (TMS)2C¼SnMe2 is formed as a short-lived intermediate by reaction of (TMS)2BrC–Sn(Y)Me2 with LiR via (TMS)2LiC– Sn(Y)Me2 (Y = F, Br, PhO; R = organyl) and its existence was demonstrated by characteristic trapping experiments including the formation of thermolabile adduct with anthracene, which was used as a ‘‘store’’ for this compound . Isolable compounds with a C¼Sn double bond are still extremely rare . The first members of this series with stability at room temperature were 264 and 265 prepared by Berndt and co-workers, both by the reaction between stannylenes and the cryptocarbene [(TMS)2C(BBut)2C] . More recently the preparation of stannaethenes 266 and 267 has been described. The X-ray structure analysis of 266 reveals a strictly planar environment of the tricoordinated tin and carbon atoms and a slight twisting of the C¼Sn bond .

TMS

But B

TMS TMS

TMS

But B

Sn TMS

B But 264

TMS TMS

TMS

B But

But N Sn SiMe2 N But

265

TMS TMS

But B B But

R1 Sn R2

266, R1 = R2 = 2-But-4,5,6-Me3C6H 267, R1 = 2-But-4,5,6-Me3C6H, R2 = (TMS)3Si

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

705

Other known compounds with tricoordinated carbon and tin atoms can better be described as Lewis base–acid adducts on account of their geometries and large C–Sn bond lengths. Examples of such compounds are zwitterionic adducts 268–270 prepared from the reaction of a nucleophilic carbene with tin(II) chloride , a diarylstannylene , or diarylplumbylene . The related species 271 and 272 were also obtained directly from a stable carbene and the corresponding stannylene and plumbylene. Each of the crystalline adducts is a monomer, having an exceptionally long central bond between the three-coordinated carbon and the M atoms.

Pri

R N+

+ –

M R R

M N N RR

Pr i

269, M = Sn, R = 2,4,6270, M = Pb, R = 2,4,6-

R N

271, M = Sn, R = ButCH2

268, M = Sn, R = Cl Pr3i C6H2 Pr3i C6H2

–



272, M = Pb, R = ButCH2



As mentioned in the previous section, reaction of an enetetramine with a coordinatively unsaturated metal complex is a standard method for the preparation of complexes with N-heterocyclic carbene ligands. Hahn and co-workers applied this strategy to the synthesis of a zwitterionic carbene–stannylene adduct via cleavage of a dibenzotetraazafulvalene by a stannylene. Thus reaction of the stannylene 273 with the tetramethyldibenzotetraazafulvalene 274 leads via C¼C bond cleavage in 274 to the carbene–stannylene adduct 275 (Scheme 63).

N NH NH N

THF, 36 h,

Sn[N(TMS)2]2

83% N

N

N

N

N

N 274

N Sn N

Toluene, rt, 24 h N

N – Sn N

+

N N

67% N

273

275

Scheme 63

The molecular structure of 275 is similar to those of the carbene–silylene adduct reported by Lappert or the carbene plumbylene adduct described by Weidenbruch . None of these species exhibits properties consistent with a C¼M double bond.

706

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

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708

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

1997JA12410 1997JOC292 1997JOM(529)3 1997JOM(529)87 1997JOM(529)107 1997JOM(529)151 1997JOM(529)177 1997JOM(530)255 1997JOM(531)47 1997JOM(541)237 1997MI1 1997MI343 1997OM3188 1997RCR225 1997S1013 1997ZN(B)674 1998CCR565 1998CEJ44 1998CEJ469 1998CEJ2571 1998CL651 1998EJI381 1998JOM(557)37 B-1998MI1 B-1998MI106 B-1998MI238 B-1998MI857 1998OM1631 1998OM3593 1998S125 1999ACR913 1999AG(E)678 1999AG(E)3727 1999CC755 1999CC1131 1999CCR(182)175 1999EJI1607 1999HAC554 1999JA519 1999JA5953 1999JOM(572)239 B-1999MI1 1999MI113 1999MI269 1999OM529 1999OM1622

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Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal 1999OM1815 1999OM3228 1999OM4216 1999OM4603 1999PS(152)153 1999TL8579 1999ZAAC(625)1813 1999ZN(B)1 2000AG(E)1610 2000CEJ1773 2000CEJ3531 2000CJC1412 2000CL1390 2000CRV39 2000EJI1185 2000EJI1253 2000EJI1811 2000EJI2425 2000JA12880 2000JCS(D)3094 2000JOM(596)3 2000JOM(598)292 2000JOM(598)304 2000JOM(613)56 2000SCI(289)754 2000ZAAC(626)1141 2001CC1208 2001CEJ987 2001EJI387 2001EJI481 2001EJI2377 2001JOM(617/618)70 2001JOM(617/618)423 2001JOM(617/618)629 2001JOM(621)261 2001MI1 2001MI163 2001MI621 2001OM1276 2001OM1504 2001OM5707 2001ZAAC(627)1241 2002AG(E)1290 2002AG(E)3367 2002CC1618 2002EJI1607 2002HAC534 2002JA2506 2002JCS(D)2852 2002JMOC(190)101 2002JOM(643/644)202

709

I. Pailhous, H. Ranaivonjatovo, J. Escudie´, J.-P. Declercq, A. Dubourg, Organometallics 1999, 18, 1622–1628. P. L. Arnold, F. G. N. Cloke, T. Geldbach, P. B. Hitchcock, Organometallics 1999, 18, 3228–3233. L. Weber, M. H. Scheffer, H.-G. Stammler, B. Neumann, W. W. Schoeller, A. Sundermann, K. K. Laali, Organometallics 1999, 18, 4216–4221. L. Weber, G. Dembeck, Organometallics 1999, 18, 4603–4607. L. Rigon, H. Ranaivonjatovo, J. Escudie, Phosphorus Sulfur 1999, 152, 153–167. P. Michel, A. Rassat, Tetrahedron Lett. 1999, 40, 8579–8581. A. J. Arduengo III, R. Krafczyk, R. Schmutzler, W. Mahler, W. J. Marshall, Z. Anorg. Allg. Chem. 1999, 625, 1813–1817. F. Breitsameter, A. Schmidpeter, H. Noeth, J. Knizek, Z. Naturforsch. Teil B 1999, 54b, 1–7. M. Mickoleit, K. Schmohl, R. Kempe, H. Oehme, Angew. Chem., Int. Ed. Engl. 2000, 39, 1610–1612. J. Schwarz, V. P. W. Bo¨hm, M. G. Gardiner, M. Grosche, W. A. Herrmann, W. Hieringer, G. Raudaschl-Sieber, Chem. -Eur. J 2000, 6, 1773–1780. F. Breitsameter, A. Schmidpeter, H. No¨th, Chem. -Eur. J. 2000, 6, 3531–3539. N. Wiberg, S. Wagner, S.-K. Vasisht, K. Polborn, Can. J. Chem. 2000, 78, 1412–1420. S. Ito, M. Yoshifuji, Chem. Lett. 2000, 1390–1391. D. Bourissou, O. Guerret, F. P. Gabbaı¨ , G. Bertrand, Chem. Rev. 2000, 100, 39–91. L. Weber, S. Kleinebekel, A. Ru¨hlicke, H.-G. Stammler, B. Neumann, Eur. J. Inorg. Chem. 2000, 1185–1191. R. Streubel, S. Priemer, F. Ruthe, P. G. Jones, Eur. J. Inorg. Chem. 2000, 1253–1259. M. Schwarz, G. Kickelbick, U. Schubert, Eur. J. Inorg. Chem. 2000, 1811–1817. L. Weber, Eur. J. Inorg. Chem. 2000, 2415–2441. M. Bouslikhane, H. Gornitzka, J. Escudie´, H. Ranaivonjatovo, H. Ramdane, J. Am. Chem. Soc. 2000, 122, 12880–12881. B. Gehrhus, P. B. Hitchcock, M. F. Lappert, J. Chem. Soc., Dalton Trans. 2000, 3094–3099. C. D. Abernethy, A. H. Cowley, R. A. Jones, J. Organomet. Chem. 2000, 596, 3–5. N. Wiberg, T. Passler, S. Wagner, K. Polborn, J. Organomet. Chem. 2000, 598, 292–303. N. Wiberg, T. Passler, S. Wagner, J. Organomet. Chem. 2000, 598, 304–312. R. Streubel, M. Hobbold, S. Priemer, J. Organomet. Chem. 2000, 613, 56–59. T. Kato, H. Gornitzka, A. Baceiredo, W. W. Schoeller, G. Bertrand, Science 2000, 289, 754–756. J. Grobe, D. Le Van, J. Winnemo¨ller, A. H. Maulitz, B. Krebs, M. La¨ge, Z. Anorg. Allg. Chem. 2000, 626, 1141–1147. S. Ito, M. Yoshifuji, J. Chem. Soc., Chem. Commun. 2001, 1208–1209. M. Mickoleit, R. Kempe, H. Oehme, Chem. -Eur. J. 2001, 7, 987–992. A. Ziegler, H. Pritzkow, W. Siebert, Eur. J. Inorg. Chem. 2001, 387–391. K. Schmohl, H. Reinke, H. Oehme, Eur. J. Inorg. Chem. 2001, 481–489. I. V. Shevchenko, R. N. Mikolenko, E. Lork, G.-V. Ro¨schenthaler, Eur. J. Inorg. Chem. 2001, 2377–2383. D. Enders, H. Gielen, J. Organomet. Chem. 2001, 617/618, 70–80. R. Streubel, S. Priemer, J. Jeske, P. G. Jones, J. Organomet. Chem. 2001, 617/618, 423–434. H. F. Ekkehardt, L. Wittenbecher, M. Ku¨hn, T. Lu¨gger, R. Fro¨hlich, J. Organomet. Chem. 2001, 617/618, 629–634. M. Po¨tter, U. Ba¨umer, M. Mickoleit, R. Kempe, H. Oehme, J. Organomet. Chem. 2001, 621, 261–266. W. A. Herrmann, Th. Weskamp, V. P. W. Bo¨hm, Adv. Organomet. Chem. 2001, 48, 1–69. E. A. Romanenko, A. M. Nesterenko, Theoretical and Experimental Chemistry 2001, 37, 163–167. M. Weidenbruch, Main Group Chem. 2001, 24, 621–631. J. C. Garrison, R. S. Simons, J. M. Talley, C. Wesdemiotis, C. A. Tessier, W. J. Youngs, Organometallics 2001, 20, 1276–1278. J. B. Diminnie, J. R. Blanton, H. Cai, K. T. Quisenberry, Z. Xue, Organometallics 2001, 20, 1504–1514. T. L. Morkin, W. J. Leigh, T. T. Tidwell, A. D. Allen, Organometallics 2001, 20, 5707–5716. J. Grobe, A. Armbrecht, D. Le Van, B. Krebs, J. Kuchinke, M. Lage, E.-U. Wurthwein, Z. Anorg. Allg. Chem. 2001, 627, 1241–1247. W. A. Herrmann, Angew. Chem., Int. Ed. Engl. 2002, 41, 1290–1309. S. Ekici, D. Gudat, M. Nieger, L. Nyulaszi, E. Niecke, Angew. Chem., Int. Ed. Engl. 2002, 41, 3367–3371. H. Hayashi, H. Sonoda, K. Fukumura, T. Nagata, J. Chem. Soc., Chem. Commun. 2002, 1618–1619. A. Weiss, H. Pritzkow, W. Siebert, Eur. J. Inorg. Chem. 2002, 1607–1614. P. L. Arnold, Heteroatom Chem. 2002, 13, 534–539. T. Kato, H. Gornitzka, A. Baceiredo, W. W. Schoeller, G. Bertrand, J. Am. Chem. Soc. 2002, 124, 2506–2512. K. M. Lee, H. M. J. Wang, I. J. B. Lin, J. Chem. Soc., Dalton Trans. 2002, 2852–2856. J. R. Blanton, T. Chen, J. B. Diminnie, H. Cai, Z. Wu, L. Li, K. R. Sorasaenee, K. T. Quisenberry, H. Pan, C.-S. Wang, S.-H. Choi, Y.-D. Wu, Z. Lin, I. A. Guzei, A. L. Rheingold, Z. Xue, J. Mol. Catal. 2002, 190, 101–108. Y. El Harouch, H. Gornitzka, H. Ranaivonjatovo, J. Escudie´, J. Organomet. Chem. 2002, 643/644, 202–208.

710

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

2002JOM(643/644)253 C. Neumann, E. Ionescu, U. Schiemann, M. Schlenker, M. Bode, F. Ruthe, P. G. Jones, R. Streubel, J. Organomet. Chem. 2002, 643/644, 253–264. 2002JOM(654)233 W. Chen, B. Wu, K. Matsumoto, J. Organomet. Chem. 2002, 654, 233–236. 2002JOM(660)121 M. Muehlhofer, T. Strassner, E. Herdtweck, W. A. Herrmann, J. Organomet. Chem. 2002, 660, 121–126. 2002JOM(663)192 M. Niehues, G. Kehr, G. Erker, B. Wibbeling, R. Fro¨hlich, O. Blacque, H. Berke, J. Organomet. Chem. 2002, 663, 192–203. 2002OL1915 I. El-Sayed, T. Guliashvili, R. Hazell, A. Gogoll, H. Ottosson, Org. Lett. 2002, 4, 1915–1918. 2002OM1531 M. Bouslikhane, H. Gornitzka, H. Ranaivonjatovo, J. Escudie´, Organometallics 2002, 21, 1531–1533. 2002OM4919 T. Baumgartner, P. Moors, M. Nieger, H. Hupfer, E. Niecke, Organometallics 2002, 21, 4919–4926. 2002OM5204 V. Ce´sar, S. Bellemin-Laponnaz, L. H. Gade, Organometallics 2002, 21, 5204–5208. 2002OM5428 J. A. Chamizo, J. Morgado, M. Castro, S. Berne`s, Organometallics 2002, 21, 5428–5432. 2002PS(177)1571 L. Weber, M. Meyer, B. Quasdorff, Phosphorus Sulfur 2002, 177, 1571–1574. 2002PS(177)1609 S. Ito, M. Yoshifuji, Phosphorus Sulfur 2002, 177, 1609–1612. 2002TA1969 M. C. Perry, X. Cui, K. Burgess, Tetrahedron Asymmetry 2002, 13, 1969–1972. 2003CEJ704 F. E. Hahn, V. Langenhahn, N. Meier, T. Lu¨gger, W. P. Fehlhammer, Chem. -Eur. J. 2003, 9, 704–712. 2003IC2572 M. Poyatos, M. Sanau´, E. Peris, Inorg. Chem. 2003, 42, 2572–2576. 2003JA1128 C. D. Abernethy, G. M. Codd, M. D. Spicer, M. K. Taylor, J. Am. Chem. Soc. 2003, 125, 1128–1129. 2003JCS(D)699 A. A. D. Tulloch, S. Winston, A. A. Danopoulos, G. Eastham, M. B. Hursthouse, J. Chem. Soc., DaltonTrans. 2003, 699–708. 2003JOM(671)183 C. A. Quezada, J. C. Garrison, C. A. Tessier, W. J. Youngs, J. Organomet. Chem. 2003, 671, 183–186. 2003OM440 M. Poyatos, P. Uriz, J. A. Mata, C. Claver, E. Fernandez, E. Peris, Organometallics 2003, 22, 440–444. 2003OM907 A. Fu¨rstner, G. Seidel, D. Kremzow, C. W. Lehmann, Organometallics 2003, 22, 907–909. 2003OM1110 M. Poyatos, J. A. Mata, E. Falomir, R. H. Crabtree, E. Peris, Organometallics 2003, 22, 1110–1114.

Functions Containing Doubly Bonded P, As, Sb, Bi, Si, Ge, B, or a Metal

711

Biographical sketch

Vadim D. Romanenko was born in Lugansk, Ukraine, in 1946. He studied at the Institute of Chemical Technology (Dnepropetrovsk) and received his Ph.D. degree there under the direction of professor S. I. Burmistrov. Since 1975 he has been working at the National Academy of Sciences of Ukraine from which he earned his Doctor of Chemistry degree in 1988. He became a full professor in 1991. He has been a visiting scientist at the Centre of Molecular and Macromolecular Studies in Lodz (Poland), the Shanghai Institute of Organic Chemistry (China), the University of Pau & des Pays de l’Adour (France), the University Paul Sabatier (France), the University California Riverside (USA). His research interests include a wide range of topics at the border between organic and inorganic chemistry, in particular the chemistry of multiply bonded heavy main group elements. He is the author of approximately 260 papers on organoelement chemistry. He is also author of numerous reviews and two monographs on low-co-ordinated phosphorus compounds.

Valentyn Rudzevich was born in Kazatin, Ukraine, in 1968. He received his Diploma degree in 1992 from Taras Shevchenko Kiev State University. Since 1992 he has been working at the Institute of Organic Chemistry of National Academy of Science of Ukraine, from which he received his Ph.D. degree under the supervision of professor V. D. Romanenko in 1997. Afterwards, he carried out postdoctoral studies at Universite´ Paul Sabatier (Toulouse, France), University of California Riverside (USA) and Johannes Gutenberg Universita¨t Mainz (Germany). On his return to Kiev, he joined the Institute of Organic Chemistry where he is presently a scientist researcher. His research interests are focused on organoelement compounds, shortlived intermediates, and co-ordination chemistry.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 661–711

6.23 Tricoordinated Stabilized Cations, Anions, and Radicals, +CX1X2X3,
CX1X2X3, and _CX1X2X3 M. BALASUBRAMANIAN Pfizer Global Research and Development, Ann Arbor, MI, USA 6.23.1 CARBON-CENTERED CATIONS BEARING THREE HETEROATOM FUNCTIONS 6.23.1.1 Introduction 6.23.1.2 Cations Bearing Three Halogens 6.23.1.3 Cations Bearing Halogen and Chalcogen Functions 6.23.1.4 Cations Bearing Halogen, Other Elements, and (Possibly) Chalcogen Functions 6.23.1.4.1 Cations bearing two halogen and one nitrogen functions 6.23.1.4.2 Cations bearing two halogen and one other heteroatom functions 6.23.1.4.3 Cations bearing one halogen, one chalcogen, and one nitrogen functions 6.23.1.4.4 Cations bearing one halogen and two nitrogen functions 6.23.1.5 Cations Bearing Three Chalcogen Functions 6.23.1.5.1 Three oxygen functions 6.23.1.5.2 Three sulfur functions 6.23.1.5.3 Three selenium functions 6.23.1.6 Cations Bearing Chalcogen and Nitrogen Functions 6.23.1.6.1 Two oxygen and one nitrogen functions 6.23.1.6.2 Two sulfur and one nitrogen functions 6.23.1.6.3 Two selenium and one nitrogen functions 6.23.1.6.4 Two different chalcogen and one nitrogen functions 6.23.1.6.5 One oxygen and two nitrogen functions 6.23.1.6.6 One sulfur and two nitrogen functions 6.23.1.6.7 One selenium and two nitrogen functions 6.23.1.7 Cations Bearing Chalcogen, Metal, and (Possibly) Nitrogen Functions 6.23.1.8 Cations Bearing Three Nitrogen Functions 6.23.1.9 Cations Bearing Nitrogen and Other Element Functions 6.23.1.10 Cations Bearing Phosphorus and Silicon Functions 6.23.2 CARBON-CENTERED CARBANIONS BEARING THREE HETEROATOM FUNCTIONS 6.23.2.1 Carbanion Bearing Three Halogens 6.23.2.2 Carbanions Bearing One Halogen and Two Sulfur Functions 6.23.2.3 Carbanions Bearing One Halogen and Two Phosphorus Functions 6.23.2.4 Carbanions Bearing Three Nitrogen Functions 6.23.2.5 Carbanions Bearing Three Sulfur Functions 6.23.2.6 Carbanions Bearing Three Phosphorus Functions 6.23.2.7 Carbanions Bearing One Phosphorus and Two Sulfur Functions 6.23.2.8 Carbanions Bearing One Nitrogen and Two Sulfur Functions 6.23.3 CARBON-CENTERED RADICALS BEARING THREE HETEROATOM FUNCTIONS

713

714 714 714 714 714 714 714 714 715 716 716 716 717 717 717 717 718 718 718 719 719 719 720 721 722 722 723 723 723 723 723 723 724 724 724

714 6.23.1

Tricoordinated Stabilized Cations, Anions, and Radicals CARBON-CENTERED CATIONS BEARING THREE HETEROATOM FUNCTIONS

6.23.1.1

Introduction

Carbocations with three heteroatom substitutents attached to carbon are popular reaction intermediates. They are stabilized by electron donation from lone pairs of electrons from heteroatoms into the vacant
-orbitals on carbon. Nitrogen is the most effective of the three common heteroatoms (O, N, S) with respect to electron pair donation. The presence of just one nitrogen function can enable the salt of a formal carbocation to be more stable and isolable. With one nitrogen atom attachment, there are two resonance hybrid structures possible, carbenium ion 1 (+ve charge on carbon) and iminium ion 2 (+ve charge at nitrogen). Such compounds are generally considered to have the charge on nitrogen. Such positively charged derivatives of compounds are considered in Chapter 6.20. When the carbocation has more than one heteroatom function attachment then there are further possibilities for charge delocalization.

6.23.1.2

Cations Bearing Three Halogens

Trihalomethyl cations CX3 (X = Br, Cl, F) have been generated at low temperature from tetrahalomethanes on reaction with antimony pentahalides, and they have been reviewed earlier . Bromochlorofluoromethylium ion has been generated from bromochlorodifluoromethane . The
-electron donor ability of fluorine is more than offset by its electron withdrawing inductive effect, thus the trifluoromethyl cation is less stable than the other trihalomethyl cations.

6.23.1.3

Cations Bearing Halogen and Chalcogen Functions

Fluoroformic acid is an intermediate in the oxidation of fluorocarbons and ozonolysis of fluoroalkenes. Its potential role in the depletion of the ozone layer in the stratosphere was explored in the early 1990s. Neutral fluoroformic acid does not exist because of its autocatalytic decomposition to HF and CO2. However, its conjugate acid and base protonated fluoroformic acid [FC(OH)+ 2 ] and fluoroformate ion ], respectively, are expected to be more stable due to its resonance stabilization. Protolytic [FCO
2 ionization of t-butyl fluoroformate with fivefold excess of FSO3H/SbF5 in SO2ClF resulted in a deep yellow solution containing the carbocation +CF(OH)2 . Bromotrifluoromethane, further reacted with H3O+ to produce the carbocation +CF2OH .

6.23.1.4 6.23.1.4.1

Cations Bearing Halogen, Other Elements, and (Possibly) Chalcogen Functions Cations bearing two halogen and one nitrogen functions

The preparative methods for dihaloiminium salts such as N,N-dimethyldihaloiminium halides 3 (X = Cl, Br, I) and pyrrolidinedichloroiminium chloride 4 have been reviewed previously . These salts are important reagents and have a wide variety of synthetic applications. No further development has been found on these types of salts.

6.23.1.4.2

Cations bearing two halogen and one other heteroatom functions

Several transition metal complexes exist in which CX2 acts as a ligand. Such metal complexes have overall positive charge and have been reviewed . No further development has been seen for these types of transition metal complexes since 1995.

6.23.1.4.3

Cations bearing one halogen, one chalcogen, and one nitrogen functions

The chlorination of N-methylbenzothiazole-2-selone 5 and 1,1-dimethylselenourea 7 with SO2Cl2 and chlorine produced corresponding benzothiazolium 6 and uronium 8 salts, respectively, and X-ray studies have been conducted for these salts .

715

Tricoordinated Stabilized Cations, Anions, and Radicals X + Y

X

NR2

Y 1

S + Cl N SO2Cl– Me 6

Se N Me 5

6.23.1.4.4

R N + X– X R 3 X = Cl, Br, F

2

S

X

X

+ R N R

X–

N + X 4

Me Me N Se H2N

Me Me N + Cl H2N

7

SeCl5–

8

Cations bearing one halogen and two nitrogen functions

Tetramethylfluoroformamidinium hexafluorophosphate (TFFH) 9 a nonhygroscopic salt, stable under ambient conditions, was obtained from 10 with excess of anhydrous KF . The salt 10 was prepared previously from tetramethylurea using phosgene. A new improved synthetic procedure for 10 from tetramethylurea using oxalyl chloride has been reported . TFFH appears to be an ideal coupling reagent for solid-phase syntheses, being readily available, inexpensive and capable of providing peptides of high quality . A new and convenient method for the solid-phase preparation of pentasubstituted guanidines involves the use of aminium/uranium salt-based reagents. These compounds have been used mainly as coupling agents in peptide synthesis and they activate the carboxyl group of the amino acids . Bispyrrolidinefluoromethylium tetrafluoroborate 11 is a convenient reagent for the solid-phase synthesis of a range of peptides incorporating sensitive amino acids and 11 has been prepared from 1,10 -carbonylbispyrrolidine 13a using oxalyl chloride . Bispiperidinechloromethylium tetrafluoroborate 12 was prepared from 1,10 -carbonylbispiperidine 13b via deoxygenation using phosgene . Pyrrolidine-1-carboxylic acid dialkylamides 14 and 15 reacted with COCl2 to form N,N-dialkyl-N-pyrrolidinochloromethylcarbenium salts 16 and 17 . 2-chloro-1,3-dimethylimidazolinium chloride 19 has been prepared from 1,3-dimethylimidazolidine-2-one 18 and oxalyl chloride . 2-Chloro-1,3-dimethylimidazolinium chloride is a powerful dehydrating agent and 19 is equivalent to dicyclohexylcarbodiimide (DCC). The advantages of 19 are low cost, nontoxic, and easy removal of product from the reaction mixture by simple washing with water. Chiral guanidines prepared from 19 can be considered as super bases due to their strong basic character . The synthetic utility of 19 has been well demonstrated as an effective dehydrating agent in the following synthetic reactions: esterification of hindered alcohol, acylation of 1,3-diones (cyclic), dehydration of oximes to nitriles (aromatic), and dehydration of benzamide to nitriles . Isocyanides, isothiocyanates, and carbodiimides were synthesized from formamides, dithiocarbamates, and thiourea, respectively . 2-Chloro-1,3-dimethylimidazolinium chloride is used as a coupling agent for the conversion of trimesitylchlorosilane to hexamesityldisilane . Further reactions of 19 are explored with L-valinol, benzamide, and methyl(S)-1-phenylethylamine to produce more useful and novel compounds . Me + N N Me Me X PF–6 or BF–4

Me

N O

14 R = Me, 15 R = Et

Cl– or BF–4

N+ N

n(H2C)

(CH2)n N

X

N +

R N Cl

13a n = 1; 13b n = 2

Me

Me N R PF6–

16 R = Me, 17 R = Et

N O

11 n = 1, X = F 12 n = 2, X = Cl

9 X = F, 10 X = Cl

R N R

(CH2)n

n(H2C)

Me

N O 18

Me

N

+

N

Cl– or BF4–

Cl 19

716

Tricoordinated Stabilized Cations, Anions, and Radicals

6.23.1.5

Cations Bearing Three Chalcogen Functions

6.23.1.5.1

Three oxygen functions

Several examples of tris(alkoxy)methylium salts were reviewed earlier and no further advances have occurred in this area since 1995 . Trimethylsilylacetylene 20 has been deprotonated with BuLi and subsequently reacted with 21 to give 1,1,1-triethoxy2-trimethylsilylpropyne 22, thus exploring the synthetic utility of triethoxycarbenium tetrafluoroborate 21 . Protonation of dimethyl carbonate by the super acids system HF, MF5 (M = As, Sb) afforded dimethoxyhydroxycarbenium hexafluorometallates 23, which are colorless, moisture sensitive salts. These salts are soluble in SO2, and are stable at
70  C for several weeks .

6.23.1.5.2

Three sulfur functions

Stable salts of carbenium ions bearing three sulfur functions have been reported. The methods for their preparation are analogous to those used for the tris(alkoxy)carbenium ions but, since it is much easier to alkylate sulfur than oxygen, a wider range of alkylating agents can be used. Substituted 1,3-dithiolane- and 1,3-dithioles-2-thiones 24 and 26 were also alkylated using various methylating agents to provide corresponding salts 25 and 27. Thiones are often alkylated with the most commonly used methylating agents such as alkyl halides and methyltrifluoromethane sulfonate , although dimethyl sulfate has been used occasionally . 4,5-Disubstituted 1,3-dithiole-2-thiones 26a and 26b were methylated using methyltrifluoromethane sulfonate to provide corresponding salts 27a and 27b in quantitative yield. Derivatives of 1,3-dethiole-2-thiones 28, 29 were methylated to the corresponding 1,3-dithiolium iodides 30, 31, and 31 underwent desulfurization with subsequent self-coupling to afford the dimeric product 32 .

OEt – EtO + BF4 OEt 21

Me Si Me Me 20

R1

R1

S

R2

S

R2

R1

S

R2

S

S + S

S Me

27

S R

R

R S + S

S

28 R = H 29 R = SMe

Me

I– or CF3SO–3

R

R

MF–6 M = As, Sb

26a, 27a R1R2 = (S–CH2CH2–S) 26b, 27b R1 = R2 = CH2–S–(C=O)Me

R S

R2

26

24a, 25a R 24b, 25b R1 = R2 = Me

R

S S

1 = R2 = H

R

23

Me

25

R

O

22

CF3SO–3 24

Me HO + O

OEt OEt OEt

R1

S + S

S

Me Me Si Me

R 30 R = H 31 R = SMe

Me S I–

R R

S

S

S

S

R R R

R 32 R = SMe

717

Tricoordinated Stabilized Cations, Anions, and Radicals

Several coupling products of substituted thienodithiolylidenefluorene 35 were prepared from substituted fluorene and thienodithiolane carbenium ion 34, which in turn was derived from thienodithiole-2-thione 33 . The degree of intramolecular charge transfer (ICT) in dithiolylidene fluorenes bearing fused thiophene has been investigated by UV-VIS spectroscopy . Tris(trifluoromethyl(chalcogenato)carbenium ions 36 and 37 were prepared from fluoro tris(trifluoromethylthio)methane and fluoro tris(trifluoromethylseleno)methane . Tris(chalcogenato)carbenium ion 38 was generated from CBr4 and ArSCu . Further reaction of tris(trifluoromethylthio)carbenium hexafluoroarsenate 36 with benzene and anisole produced benzophenone and 4,40 -dimethoxybenzophenone, which are products of hydrolysis of the diphenylmethane intermediate .

6.23.1.5.3

Three selenium functions

Tris(trifluoromethylseleno)carbenium hexafluoroarsenate 37 was prepared from tetrakistrifluoromethylselenylmethane and is stable at
20  C. Trisisoopropylbenzene selenide reacted with tetrabromomethane to form tris(triisopropylbenzene)selenide 39 .

S

S S

S

CF3SO–3

S + S

33

S Me

Ar X X

+

XCF3

37 X = Se,

6.23.1.6 6.23.1.6.1

Me Me

X

Ar PF6–

S 35

34

F3CX + XCF3

36 X = S, AsF6–

S S

Ar

Ar =

Me *

S

Me

38 X = S, AsF6– 39 X = Se, PF6–

Me Me

Cations Bearing Chalcogen and Nitrogen Functions Two oxygen and one nitrogen functions

Mono-O-protonated carbamic acids and N-methyl carbamate were prepared using super acids (FSO3H/ SO2ClF and FSO3H:SbF5/SO2ClF) at
78  C, and these salts were characterized by 1H, 13C, 15N NMR spectroscopy . A stable salt of 1,9-diethoxy-1-methoxy-3,5,7,9-tetraphenyl-2,4,6,8tetraazanonatetraenylium hexachloroantimonate 41 was prepared from the corresponding ester 40, by regioselective O-alkylation with triethyloxonium hexachloroantimonate . Further reaction of dimethylaminodiethoxycarbenium tetrafluoroborate 42 with N,N-dimethylamine produced bis(dimethylamino)diethoxymethane .

6.23.1.6.2

Two sulfur and one nitrogen functions

Methylations of few cyclic dithiocarbamates with dimethyl sulfate yielded corresponding thiocarbamate salts and have been reviewed previously . Dithiocarbamate salts 45 and 46 are most often prepared by S-alkylation of dithiocarbamates 43 and 44 .

718

Tricoordinated Stabilized Cations, Anions, and Radicals

6.23.1.6.3

Two selenium and one nitrogen functions

Reaction of 2-chloro-1,3-diselenoazolium tetrafluoroborate 47 with morpholine to form 1,3diselenazole-2-morpholinium salt 48 has been reported .

6.23.1.6.4

Two different chalcogen and one nitrogen functions

Alkylation of 3-methyl-5-phenyl-3H-1,3,4-oxadiazole-2-thione 49 with MeI produced salt 50 . Alkylation of diethylthiocarbamic acid O-p-tolyl ester 51 with triethyloxonium tetrafluoroborate produced a moisture sensitive, colorless solid stable salt 52 .

6.23.1.6.5

One oxygen and two nitrogen functions

Alkylation of substituted ureas with 21 primarily produced O-alkylated stable and isolable uronium salts. This work has already been reviewed . It is interesting to note that in some cases, N-alkylation of tetraalkylurea competes with O-alkylation. Thus an alternative synthetic strategy is employed for the preparation of uronium salts starting from N,N,N0 ,N0 -tetramethylchloroformadinium chloride whereby N-alkylation can be avoided. N,N,N0 ,N0 -Tetramethyl(succinimido)uronium tetrafluoroborate 54 and 2-(1H-benzotriazol-1yl)-1,1,3,3-tetramethyluronium hexafluorophosphate 56 have been used as coupling agents in solid-phase peptide synthesis. They are excellent activating agents and reduce racemization during condensation of peptide segments. They are useful tools for the formation of active esters suitable for coupling in mixed aqueous or organic media.

O

Et R + O

O R

O Et

40

O

N

N

Me2N + OEt

R=

SbCl–

6

OEt

BF 4–

42

41

Me N

S Me

Me N R

S

R

43 R = H, 44 R = Me

S N N

O

N

N

Me

S Me + I– S Me

Se Cl + – Se BF 4

45 R = H, 46 R = Me

Me S + N N

O

Me I–

Se N + Se 48

47

Me

Me N

Me

S

N

O

Me

S BF–4

+ O

Me 49

50

O BF–4

Me 52

51

N

O

N OH

Me Me O N Me + N N Me O

O

O 53

BF4– 54

N N N N – K+ O 55

N

PF–6 Me O Me N + N Me Me 56

Tricoordinated Stabilized Cations, Anions, and Radicals

719

N-Hydroxysuccinimide 53 reacted with 10 to form N,N,N0 ,N0 -tetramethyl(succinimido)uronium tetrafluoroborate 54 . Several esterification reactions have been reported in which N,N,N0 ,N0 -tetramethyl(succinimido)uronium tetrafluoroborate 54 is used as a coupling agent. The salt shown in 54 has been used as a feed stock to produce several other useful coupling agents . 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate 56 was prepared from benzotriazole-N-oxide 55 using 10 and the salt given in 56 is used as a coupling agent for several esterification reactions .

6.23.1.6.6

One sulfur and two nitrogen functions

There has been considerable interest in the usage of isothiuronium salts in membranology and in organic synthesis. These salts are used to regulate free radical oxidation in biological membranes. Functional transformation of CH2X to CH2SH via isothiuronium salt has been shown to have a great deal of synthetic utility in organic synthesis. S-Alkylation of tetramethylthiourea 57, with MeI gave isothiuronium salt 58 . Salt of disulfide 59 was obtained from 57 via oxidation with bromine . 2-Bromo-2H-1,4-benzoxazin-3(4H)-one 60 and 2-bromo-2H-1,4-benzothiazin-3(4H)-one 61 were converted into corresponding isothiuronium salts 62 and 63 by reaction with thiourea in acetone . Further, these salts were converted to the corresponding mercapto derivatives by alkaline hydrolysis. Isothiuronium salt 65 was obtained from 3-chloro-2-chloromethylpropene 64 and thiourea via S-alkylation . The S-alkylation of thiophosphate 66 by thiourea, followed by ring opening, produced thiuronium salt 67 . Bicyclic thiophosphate 68 reacted with thiourea to provide a high yield of betaine 69, which is of certain bioregulating interest as a radioprotector, and the overall reaction is a thione-thiol isomerization (ring-opening products) . Disodium[(3-methylthioureido)methylene]bisphosphonate 70 is easily alkylated in aqueous solution with MeI to give stable and isolable thiuronium salt 71 . 4-Nitrophenylisothiuronium salt was obtained from 4-nitrobenzenethiol and NH2CN . 6,60 -Bischloromethyl-[2,20 ]bipyrazinyl isothiuronium salt 72 was obtained from 6,60 -bischloromethyl-[2,20 ]bipyrazine and thiourea . Tetramethyluronium and -thiouronium salts 75 and 76 were prepared from N-hydroxy-2-oxopyridine 73 and N-hydroxy-2-mercaptopyridine 74, respectively . Novel carbanion ionophores based on thiuronium derivative 78 have been prepared via S-alkylation of N-benzyl-N-butylthiourea 77 using MeI, and their application to ion selective electrodes has been examined .

6.23.1.6.7

One selenium and two nitrogen functions

Synthesis of dipyridoimidazolone 80 from 6H-dipyridoimidazole-6-selone 79, was accomplished via Se-alkylation of 79 with MeI followed by hydrolysis of the resulting salt, 6-(methylselan)dihydroimidazolium iodide 81, produced 80 .

6.23.1.7

Cations Bearing Chalcogen, Metal, and (Possibly) Nitrogen Functions

General methods for the preparation of cationic carbene complexes of mercury and platinum complex have been reviewed . Lewis acid adducts of stable nucleophilic carbene 82 with various metals have been reported .

720

Tricoordinated Stabilized Cations, Anions, and Radicals S

NMe2

Me2N

S

Me Br–

Me2N + NMe2

2Br– S NMe2 S + NMe2

58

57

Br

X

Me2N + Me2N

X N H

O

59

S + O

NH2 NH2

Br –

62 X = O, 63 X = S

60 X = O, 61 X = S

H2N + NH2 O H2N Cl

S

+ H2N

Cl

S 2Cl–

64

O O P S O

O

65

S + H2N O S P O O–

O O O

S O

N

Me

P ONa O OH

H H N + N

Me

S

O OH P – O

P ONa O OH

+

71

Me

+ Me N X N Me OH BF4–

N OH

S

S

N

H

N H Bu

N

Ph

H

Me

N + N I– Bu

Ph

+

H2N

Me X

S

2Cl–

O OH P ONa

70

N N

S

NH2 72

73 X = O 74 X = S

N

77

75 X = O 76 X = S

N N + X

79 X = Se, 80 X = O

6.23.1.8

H N

69

N

H2N

Me

O

H N

67

O

68

H2N

O P S O–

O

66

H2N O O P O S

S

O

O

NH2 + NH2

I–

78

N

Se Me 81

Cations Bearing Three Nitrogen Functions

Preparative methods for guanidines have been described in Chapter 6.21. Guanidines are strong bases and also excellent nucleophiles. Several guanidium salts have been prepared by protonation or alkylation of guanidine . Tris(pyrrolidine)carbenium chloride 83 has been prepared from fluorobis-(1-pyrrolidinyl)carbenium chloride 11 by reacting with pyrrolidine . Reaction of phenylbis(3-aminobenzene)phosphine 84 with dimethylcyanamide 85 provided guanidinium phosphines 86 in high yield . Deprotonation of PhCOCHPhCO2Me 87 with tetrakis(dimethylamine)methane led to a stable salt 88, which belongs to a very rare species of salts that consists of a heteroatom stabilized carbocation and a heteroatom stabilized carbanion . Triazidocarbenium salt is prepared from tetrachloromethane using NaN3 , and 89 is ideally suited for high energy density material such as propellants and explosives. Conversion of 89 to more energetic salts containing anions such as [
N(NO2)2] and (ClO4
)] has been reported . Quinolinotriazole-N-oxide 90 was converted into the corresponding guanidinium salt 91 using 10 .

721

Tricoordinated Stabilized Cations, Anions, and Radicals 6.23.1.9

Cations Bearing Nitrogen and Other Element Functions

N,N-Dimethylformamide acetal reacted with elemental selenium to give selenocarbonic acid derivative 92, which was further converted into N,N-dimethylcarbamidic acid Se-methylester 93 via alkylation with MeI . Alkylation of N-methylbenzoselenazole-2-thione 94 and 3,3-ethylenebis(benzoselenoazole-2-thione) 96 with the strong alkylating agent, diethoxycarbonium tetrafluoroborate, produced corresponding salts 95 and 97, respectively .

+

N

N

Li2– + O Li2–

N

N

+

O+

N N C + N Cl–

Ph P

H2N

NH2

84 83

82

Me2N + NMe2

Me N CN

Ph P

HN

Me

Me2N +

O

NMe2

O

Ph

NH

Me O

2Cl– 85

Ph

87

86

Me2N + +C(NMe

–O

N3 + N3

Ph

2 )3

O

Ph

Me

N

N3 SbCl –6

N

89

90

O 88

MeO

MeO + Me2N

Se Me2N

Se Me

N N OH

Me N

I–

Me BF4– N + S Se

S Se

93

92

94

95

S 2BF4– N

S N

Se

S

N + N N N O– 91

N

+

Se

N +

Se

S Se 97

96

..

+ P C N –

P C N

+ P C N BF4–

98

98a

MeO

OMe S 99

MeO + OMe SMe 100

X–

NMe2 PF6–

722

Tricoordinated Stabilized Cations, Anions, and Radicals

Few cationic carbene complexes and their salts have been prepared in which the cation bears nitrogen and one phosphorus functions. Synthesis, structure, stability, and reactivity of (amino) (phosphino) carbenes has been reported . Treatment of carbene, [(t-Bu)2PCN (i-Pr)2] 98 with 1 equiv. of BF3Et2O, led to quantitative formation of carbene complex 98a, which has been characterized by NMR spectroscopy . Carbenium ion 100 bearing sulfur and two oxygen functions has been produced via S-alkylation of thiocarbonic acid O,O0 -dimethyl ester 99 with iodomethane .

6.23.1.10

Cations Bearing Phosphorus and Silicon Functions

The C-alkylation of 1,3-diethyl-4,5-dimethylimidazol-2-ylidene 101 with iodotrimethylsilane produced 1,3-diethyl-4,5-dimethyl-2-(trimethylsilyl)imidazolium iodide 102 . Rapid valence isomerization of phosphaalkene-phosphenium cation 103a to cationic diphosphene 103b was observed and 103b was characterized by 31P NMR spectroscopy, but not isolated . 1,2-Silyl migration in aromatic carbenes via intermolecular silyl exchange has been reported . Since aromatic carbenes are very good nucleophiles, attack of triphenyltriazole carbene 104 on the silyl group of cation 105 resulting in the formation of C-silyl substituted triazolium salt 106 along with methyltriazole . Several crystalline adducts 109 were prepared from benzimidazole carbene 107 by reacting with derivatives of 108 (silylene germylene, stannylene, or plumbylene). The C
M bond is electrostatic in nature with the carbene moiety as an electron donor and the metal fragment as an electron acceptor .

Et N

Et Me N + Si Me N Me Et

..

N Et 101

I–

Et2N Et2N

103a

102

Me Si Me

N

..

N N Ph

Ph

Ph Me N Si N N Me Ph

105

104

N N

107

6.23.2

103b

+

N + N N CF3SO3– Me

..

P P N

CF3SO3–

CF3SO3–

Ph Ph

Et2N + Et2N

+ P P N

N M N

108 M = Si, Ge, Sn, Pb

CF3SO3–

106

N + N

N M– N

109 M = Si, Ge, Sn, Pb

CARBON-CENTERED CARBANIONS BEARING THREE HETEROATOM FUNCTIONS

Carbanionic carbons bearing three different heteroatom functions were not covered in the earlier review . The current review includes several such carbanionic carbon-

Tricoordinated Stabilized Cations, Anions, and Radicals

723

bearing nitrogen, phosphorus, and sulfur functions. They are stable at low temperature, isolable, and are useful intermediates in organic synthesis. Attachment of phosphorus and sulfur functions to carbanionic carbon causes an increase in carbanion stability due to an overlap of the unshared electron pair with an empty d-orbital (p

d
bonding). Electron withdrawing groups such as NO2 at the -position also stabilize carbanions.

6.23.2.1

Carbanion Bearing Three Halogens

The N-trimethylsilylimidophosphenous acid derivative from 2,2,6,6-tetramethylpiperidine reacts with bromotrichloromethane readily to afford the stable salt 110. The ion pair 110 is stable and provides an environment for sterically favorable nucleophilic substitution of the trichloromethide anion rather than bromide ion. The possibility that this reaction proceeds via a radical mechanism cannot be ruled out .

6.23.2.2

Carbanions Bearing One Halogen and Two Sulfur Functions

The 2,2,4,4-tetrabromo-1,3-dithietan-1,1,3,3-tetroxide 111 is cleaved by tris(dimethylamine)sulfonium hexafluoride silicate 112 to form the intermediate salt 113. The fluoride ion from 113 can be abstracted by SiF4 and quinuclidine and the resulting perhalogenated mesylsulfene (Br3SO2C(Br)¼SO2 is stabilized by S-coordinated quinuclidine .

6.23.2.3

Carbanions Bearing One Halogen and Two Phosphorus Functions

Phosphonoalkylation of acylchlorophosphinate 114 in the presence of excess of LDA leads to direct generation of stable lithiated methylenediphosphonate anion 115. Further 115 can be either protonated in acidic medium to provide tetrasubstituted methylenediphosphonate or alkylated. When aliphatic or aromatic aldehydes are added, spontaneous formation of vinyl phosphonates is observed .

6.23.2.4

Carbanions Bearing Three Nitrogen Functions

Deprotonation of trinitromethane with tetrabutylammonium hydroxide results in trinitromethide 116a. Deprotonation of trinitromethane with benzyltrimethylammonium hydroxide provides 116b, which is unstable even at
15  C and it undergoes decomposition with explosive release of gases when stored in the dark at room temperature .

6.23.2.5

Carbanions Bearing Three Sulfur Functions

Interaction of tris(fluorosulfonyl)methane and tris(trifluoromethylsulfonyl) with aryldiazonium chloride in water leads to the formation of stable water-insoluble salts 117a and 117b, respectively . Benzenediazonium bis(fluorosulfonyl)phenoxysulfonyl methanide 118, a colorless crystalline solid stable at 0  C is produced by simple mixing of benzenediazonium chloride with bis(fluorosulfonyl)phenoxysulfonylmethane .

6.23.2.6

Carbanions Bearing Three Phosphorus Functions

Bis(diphenylphosphino)diphenylthiophosphorylmethane is readily deprotonated with LiOH to produce the carbanion 119 . Tetrabutylammonium tris(diphenylthiophosphinoyl)methide 120 has been produced from tris(diphenylthiophosphinoyl)methane and isolated as a stable solid, which is a useful synthetic intermediate in the formation of cage complexes via coordination with metal cations .

724

Tricoordinated Stabilized Cations, Anions, and Radicals

6.23.2.7

Carbanions Bearing One Phosphorus and Two Sulfur Functions

Deprotonation of bis(ethylsulfanylmethyl) phosphonic acid diethyl ester and of bis(benzenesulfonyl)-diphenyloxoposphinyl methane produces salts 121 and 122, respectively . Trifluoromethylsulfonylphenylsulfonyldiphenylphosphinoyl methane reacts with triphenylphosphine to form salt 123, which is protonated on the phosphorus. However, with diphenylphosphinous acid, diethylamideaminophosphine affords phosphonium salt 124, which is protonated on the nitrogen .

6.23.2.8

Carbanions Bearing One Nitrogen and Two Sulfur Functions

Bis(phenylsulfonyl)diazomethane is a possible source for the production of an exceptionally electrophilic carbene, bis(phenylsulfonyl)carbene and its chemical properties were studied in the late 1990s. Treatment of bis(phenylsulfonyl)diazomethane with triphenylphosphine yields the stable phosphazine 125 .

6.23.3

CARBON-CENTERED RADICALS BEARING THREE HETEROATOM FUNCTIONS

A few known stable carbon-centered radicals bearing three heteroatom functions have been reviewed . No carbon-centered radicals bearing three heteroatom functions can be regarded as ‘‘stable’’ in that they cannot be isolated and handled. But a few such radicals have significant lifetimes ranging from a few seconds to a few hours in solution . These radicals bear silicon, phosphorus, or sulfur substitutents and their increased lifetime can be due to steric factors rather than to electron delocalization.

Br N P N Si +

Cl Cl – Cl

NMe2 S Me2N + NMe2 SiF6–

FO2S – SO2CBr3

111

112

113

110

NO2 _

O O P O

O EtO O P O Li+ O P OEt Cl

Cl

O2N – NO2

116b = NCH2PhMe3

+S(NMe

SO2X

SO2Ph FO2S – SO2F

PhN2+

PhN2+

117a, X = F; 117b, X = CF3

S Ph P Ph

S Ph P Ph

O EtO P OEt

O Ph P Ph

Ph2P – PPh2

Ph2P – PPh2 S S

EtS – SEt

PhO2S – SO2Ph

PhN+2

+NBu

121

122

+

Li

+NBu

4

120

119

PPh2

+ N=NPPh3

2)3

XO2S – SO2X

116a = +NBu4 +

115

114

Br

Br O Br S O O S Br O Br

OEt

118

PPh2 F3CO2S – SO2Ph + HPPh3

4

123

OEt

F3CO2S – SO2Ph + Ph2PNHEt2

PhO2S – SO2Ph

X P OEt SMe

S X P OEt SMe

124

125

126

127

SR

.

Tricoordinated Stabilized Cations, Anions, and Radicals

725

The tris(trimethylsilyl)methyl radical _C(TMS)3 can be generated by decomposition of [(TMS)3C]2Hg or by reduction of (TMS)3CI . This radical is long-lived in solution. A number of carbon radicals bearing three sulfur functions can also be described as persistent, among them C(SCF3), which is generated reversibly from its dimer at room temperature , and _C(SCF3)2SC6F5, which is produced from its dimer at 140–190  C . A number of other radicals bearing three sulfur functions or two sulfur and one silicon functions can be produced by the thermal dissociation of their dimers . A series of persistent radicals 126 has been produced by the reaction of the dithioesters 127 with a wide range of radicals R_, including MeS_, Me_, and Ph3Pb_ . Since 1995, one or two such radicals have been reported in the literature. The reduction of phosphoryl and thiophosphoryl formates, monothioformates and dithioformates have been studied by means of cyclic voltametry and electron paramagnetic resonance (EPR) spectroscopy data were obtained for these salts . Electron transfer reactions were studied between NO
and halotrifluoromethane in the gas phase and the formation of F2CNO radical has been observed .

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727

Biographical sketch

Marudai Balasubramanian was born in Trichy, India. He obtained his B.Sc. from PEVR College/Madras University, Trichy; his M.Sc. degree at Vivekananda College, Chennai; and his Ph.D. degree in organic chemistry from the Indian Institute of Technology, Chennai, India in 1987. He was briefly a Research Associate at ICI India Ltd., India. His postdoctoral work was conducted with Dr. A. R. Katritzky, Department of Chemistry, University of Florida, Gainesville, FL (1988–1992). During this period, he acquired an in-depth knowledge of various aspects of heterocyclic chemistry and his main research work was concentrated on reactions in hot water. He then worked as a Research Chemist/Research Associate for ten years at Reilly Industries Inc., Indianapolis, IN. His research interests include synthesis of heterocyclic compounds particularly pyridine derivatives, synthesis of intermediates for pharmaceuticals, agrochemicals, performance products, and heterocyclic polymers. In 2002, he joined Pfizer Inc, Ann Arbor, MI as an Information Scientist providing chemistry/patent information to scientists and attorneys.

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Comprehensive Organic Functional Group Transformations 2 ISBN (set): 0-08-044256-0 Volume 6, (ISBN 0-08-044258-7); pp 713–727